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John L R Rubenstein - One of the best experts on this subject based on the ideXlab platform.
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LacZ-reporter mapping of Dlx5/6 expression and genoarchitectural analysis of the postnatal mouse prethalamus.
eScholarship University of California, 2021Co-Authors: Puelles Luis, Diaz Carmen, Stühmer Thorsten, Ferran, José L, Martínez-de La Torre, Margaret, John L R RubensteinAbstract:We present here a thorough and complete analysis of mouse P0-P140 prethalamic histogenetic subdivisions and corresponding nuclear derivatives, in the context of local tract landmarks. The study used as fundamental material brains from a transgenic mouse line that expresses LacZ under the control of an intragenic enhancer of Dlx5 and Dlx6 (Dlx5/6-LacZ). Subtle shadings of LacZ signal, jointly with pan-DLX immunoreaction, and several other ancillary protein or RNA markers, including Calb2 and Nkx2.2 ISH (for the prethalamic eminence, and derivatives of the rostral zona limitans shell domain, respectively) were mapped across the prethalamus. The resulting model of the prethalamic region postulates tetrapartite rostrocaudal and dorsoventral subdivisions, as well as a tripartite radial stratification, each cell population showing a characteristic molecular profile. Some novel nuclei are proposed, and some instances of potential tangential cell migration were noted
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gabaergic interneuron differentiation in the basal forebrain is mediated through direct regulation of glutamic acid decarboxylase isoforms by dlx homeobox transcription factors
The Journal of Neuroscience, 2017Co-Authors: Qingping Zhou, Jamie Zagozewski, Inma Cobos, John L R Rubenstein, Shunzhen Zhang, Sara Japoni, Jerry Vriend, Tracie Parkinson, David D. EisenstatAbstract:GABA is the key inhibitory neurotransmitter in the cortex but regulation of its synthesis during forebrain development is poorly understood. In the telencephalon, members of the distal-less (Dlx) homeobox gene family are expressed in, and regulate the development of, the basal ganglia primodia from which many GABAergic neurons originate and migrate to other forebrain regions. The Dlx1/Dlx2 double knock-out mice die at birth with abnormal cortical development, including loss of tangential migration of GABAergic inhibitory interneurons to the neocortex (Anderson et al., 1997a). We have discovered that specific promoter regulatory elements of glutamic acid decarboxylase isoforms (Gad1 and Gad2), which regulate GABA synthesis from the excitatory neurotransmitter glutamate, are direct transcriptional targets of both DLX1 and DLX2 homeoproteins in vivo Further gain- and loss-of-function studies in vitro and in vivo demonstrated that both DLX1 and DLX2 are necessary and sufficient for Gad gene expression. DLX1 and/or DLX2 activated the transcription of both Gad genes, and defects in Dlx function disrupted the differentiation of GABAergic interneurons with global reduction in GABA levels in the forebrains of the Dlx1/Dlx2 double knock-out mouse in vivo Identification of Gad genes as direct Dlx transcriptional targets is significant; it extends our understanding of Dlx gene function in the developing forebrain beyond the regulation of tangential interneuron migration to the differentiation of GABAergic interneurons arising from the basal telencephalon, and may help to unravel the pathogenesis of several developmental brain disorders.SIGNIFICANCE STATEMENT GABA is the major inhibitory neurotransmitter in the brain. We show that Dlx1/Dlx2 homeobox genes regulate GABA synthesis during forebrain development through direct activation of glutamic acid decarboxylase enzyme isoforms that convert glutamate to GABA. This discovery helps explain how Dlx mutations result in abnormal forebrain development, due to defective differentiation, in addition to the loss of tangential migration of GABAergic inhibitory interneurons to the neocortex. Reduced numbers or function of cortical GABAergic neurons may lead to hyperactivity states such as seizures (Cobos et al., 2005) or contribute to the pathogenesis of some autism spectrum disorders. GABAergic dysfunction in the basal ganglia could disrupt the learning and development of complex motor and cognitive behaviors (Rubenstein and Merzenich, 2003).
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Development/Plasticity/Repair Dlx5 and Dlx6 Regulate the Development of Parvalbumin-Expressing Cortical Interneurons
2013Co-Authors: Yanling Wang, Thomas Lufkin, Jason E Long, Rosanne C Estrada, Tomas Roztocil, Karl Deisseroth, Scott C Baraban, Catherine A. Dye, Vikaas Sohal, John L R RubensteinAbstract:Dlx5 and Dlx6 homeobox genes are expressed in developing and mature cortical interneurons. Simultaneous deletion of Dlx5 and 6 results in exencephaly of the anterior brain; despite this defect, prenatal basal ganglia differentiation appeared largely intact, while tangential migration of Lhx6 � and Mafb � interneurons to the cortex was reduced and disordered. The migration deficits were associated with reduced CXCR4 expression. Transplantation of mutant immature interneurons into a wild-type brain demonstrated that loss of either Dlx5 or Dlx5&6 preferentially reduced the number of mature parvalbumin � interneurons; those parvalbumin � interneurons that were present had increased dendritic branching. Dlx5/6 �/ � mice, which appear normal histologically, show spontaneous electrographic seizures and reduced power of gamma oscillations. Thus, Dlx5&6 appeared to be required for development and function of somal innervating (parvalbumin � ) neocortical interneurons. This contrasts with Dlx1, whose function is required for dendrite innervating (calretinin � , somatostatin � , and neuropeptide Y � ) interneurons (Cobos et al., 2005)
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dlx5 and dlx6 regulate the development of parvalbumin expressing cortical interneurons
The Journal of Neuroscience, 2010Co-Authors: Yanling Wang, Thomas Lufkin, Catherine Dye, Vikaas S Sohal, Jason E Long, Rosanne C Estrada, Tomas Roztocil, Karl Deisseroth, Scott C Baraban, John L R RubensteinAbstract:Dlx5 and Dlx6 homeobox genes are expressed in developing and mature cortical interneurons. Simultaneous deletion of Dlx5 and 6 results in exencephaly of the anterior brain; despite this defect, prenatal basal ganglia differentiation appeared largely intact, while tangential migration of Lhx6+ and Mafb+ interneurons to the cortex was reduced and disordered. The migration deficits were associated with reduced CXCR4 expression. Transplantation of mutant immature interneurons into a wild-type brain demonstrated that loss of either Dlx5 or Dlx5&6 preferentially reduced the number of mature parvalbumin+ interneurons; those parvalbumin+ interneurons that were present had increased dendritic branching. Dlx5/6+/− mice, which appear normal histologically, show spontaneous electrographic seizures and reduced power of gamma oscillations. Thus, Dlx5&6 appeared to be required for development and function of somal innervating (parvalbumin+) neocortical interneurons. This contrasts with Dlx1, whose function is required for dendrite innervating (calretinin+, somatostatin+, and neuropeptide Y+) interneurons (Cobos et al., 2005).
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arcuate nucleus expression of nkx2 1 and dlx and lineages expressing these transcription factors in neuropeptide y proopiomelanocortin and tyrosine hydroxylase neurons in neonatal and adult mice
The Journal of Comparative Neurology, 2009Co-Authors: Cindy L Yee, Marc Ekker, Stewart A Anderson, Yanling Wang, John L R RubensteinAbstract:Despite its small size, the arcuate nucleus of the hypothalamus has a critical role in regulating energy homeostasis. We have begun to define genetic approaches to express genes in specific cell types within the developing arcuate nucleus, to allow precise molecular perturbations of these cells. Furthermore, our analysis aims to contribute to defining the transcriptional networks that regulate the development of function of the arcuate neurons. Here, we define the neuronal cells types within the arcuate that express Nkx2.1 and Dlx homeobox genes. In addition, we used mice expressing Cre recombinase from the Dlx5/6 intergenic enhancer (Dlx5/6i) and from the Nkx2.1 locus to follow the fate of embryonic cells expressing these genes within the arcuate nucleus. We demonstrate that NKX2.1+ cells and their lineages are broadly expressed in arcuate neurons [γ-aminobutyric acid (GABA)+, neuropeptide Y (NPY)+, proopiomelanocortin (POMC)+, tyrosine hydroxylase (TH)+] and glia (tanycytes). On the other hand, DLX+ cells and their lineages mark only GABA+ and TH+ (dopaminergic) neurons, and Dlx1–/– mutants have fewer TH+ neurons. These results have implications for the genetic control of arcuate development and function and for the utility of the Nkx2.1-Cre and Dlx5/6i-Cre mouse lines to alter gene expression in the developing arcuate. J. Comp. Neurol. 517:37–50, 2009. © 2009 Wiley-Liss, Inc.
Maria I Morasso - One of the best experts on this subject based on the ideXlab platform.
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DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo
Cell Death & Differentiation, 2014Co-Authors: J Isaac, J Erthal, J Gordon, O Duverger, A C Lichtler, G S Stein, J B Lian, Maria I MorassoAbstract:Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. DLX3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5 , Dlx6 , Runx2 and Sp7 as well as genes important to mineral deposition ( Ibsp , Enpp1 , Mepe ) and bone turnover ( Opg ). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation.
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neural crest deletion of DLX3 leads to major dentin defects through down regulation of dspp
Journal of Biological Chemistry, 2012Co-Authors: Olivier Duverger, Jane B Lian, Ariane Berdal, Joonsung Hwang, Angela Zah, Juliane Isaac, Hongwei Sun, Anne K Bartels, Maria I MorassoAbstract:During development, DLX3 is expressed in ectodermal appendages such as hair and teeth. Thus far, the evidence that DLX3 plays a crucial role in tooth development comes from reports showing that autosomal dominant mutations in DLX3 result in severe enamel and dentin defects leading to abscesses and infections. However, the normal function of DLX3 in odontogenesis remains unknown. Here, we use a mouse model to demonstrate that the absence of DLX3 in the neural crest results in major impairment of odontoblast differentiation and dentin production. Mutant mice develop brittle teeth with hypoplastic dentin and molars with an enlarged pulp chamber and underdeveloped roots. Using this mouse model, we found that dentin sialophosphoprotein (Dspp), a major component of the dentin matrix, is strongly down-regulated in odontoblasts lacking DLX3. Using ChIP-seq, we further demonstrate the direct binding of DLX3 to the Dspp promoter in vivo. Luciferase reporter assays determined that DLX3 positively regulates Dspp expression. This establishes a regulatory pathway where the transcription factor DLX3 is essential in dentin formation by directly regulating a crucial matrix protein.
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DLX3 is a crucial regulator of hair follicle differentiation and cycling
Development, 2008Co-Authors: Joonsung Hwang, Taraneh Mehrani, Sarah E Millar, Maria I MorassoAbstract:Dlx homeobox transcription factors regulate epidermal, neural and osteogenic cellular differentiation. Here, we demonstrate the central role of DLX3 as a crucial transcriptional regulator of hair formation and regeneration. The selective ablation of DLX3 in the epidermis results in complete alopecia owing to failure of the hair shaft and inner root sheath to form, which is caused by the abnormal differentiation of the cortex. Significantly, we elucidate the regulatory cascade that positions DLX3 downstream of Wnt signaling and as an upstream regulator of other transcription factors that regulate hair follicle differentiation, such as Hoxc13 and Gata3. Colocalization of phospho-Smad1/5/8 and DLX3 is consistent with a regulatory role for BMP signaling to DLX3 during hair morphogenesis. Importantly, mutant catagen follicles undergo delayed regression and display persistent proliferation. Moreover, ablation of DLX3 expression in the telogen bulge stem cells is associated with a loss of BMP signaling, precluding re-initiation of the hair follicle growth cycle. Taken together with hair follicle abnormalities in humans with Tricho-Dento-Osseous (TDO) syndrome, an autosomal dominant ectodermal dysplasia linked to mutations in the DLX3 gene, our results establish that DLX3 is essential for hair morphogenesis, differentiation and cycling programs.
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molecular consequences of a frameshifted DLX3 mutant leading to tricho dento osseous syndrome
Developmental Biology, 2008Co-Authors: Olivier Duverger, Mohammad Q Hassan, Jane B Lian, Delia Lee, Susie X Chen, Frederic Jaisser, Maria I MorassoAbstract:The homeodomain protein Distal-less-3 (DLX3) plays a crucial role during embryonic development. This transcription factor is known to be essential for placental formation and to be involved in skin and skeletal organogenesis. In humans, a frameshift mutation in the coding sequence of the DLX3 gene results in an ectodermal dysplasia called Tricho-Dento-Osseous syndrome (TDO). The main features of this autosomal dominant disorder are defects in hair, teeth, and bone. To investigate the functional alterations caused by the mutated DLX3(TDO) isoform ex vivo, we used tetracycline-inducible osteoblastic and keratinocyte cell lines and calvarial derived osteoblasts in which the expression of DLX3(WT) and/or DLX3(TDO) could be regulated and monitored. Immunocytochemical analysis revealed that both DLX3(WT) and DLX3(TDO) recombinant proteins are targeted to the nucleus. However, as demonstrated by electrophoresis mobility shift assay, DLX3(TDO) is not able to bind to the canonical DLX3 binding site. Furthermore, we demonstrate that the frameshifted C-terminal domain in DLX3(TDO) is accountable for the loss of DNA binding activity because the C-terminal domain in DLX3(WT) is not required for DNA binding activity. Although DLX3(TDO) alone cannot bind to a DLX3 responsive element, when DLX3(WT) and DLX3(TDO) are co-expressed they form a complex that can bind DNA. Concomitant with the inability to bind DNA, DLX3(TDO) has a defective transcriptional activity. Moreover, the transcriptional activity of DLX3(WT) is significantly reduced in the presence of the mutated isoform, indicating that DLX3(TDO) has a dominant negative effect on DLX3(WT) transcriptional activity.
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bmp2 commitment to the osteogenic lineage involves activation of runx2 by DLX3 and a homeodomain transcriptional network
Journal of Biological Chemistry, 2006Co-Authors: Mohammad Q Hassan, Rahul S Tare, Matthew Mandeville, Maria I Morasso, Amjad Javed, Andre J Van Wijnen, Janet L Stein, Gary S SteinAbstract:Several homeodomain (HD) proteins are critical for skeletal patterning and respond directly to BMP2 as an early step in bone formation. RUNX2, the earliest transcription factor proven essential for commitment to osteoblastogenesis, is also expressed in response to BMP2. However, there is a gap in our knowledge of the regulatory cascade from BMP2 signaling to the onset of osteogenesis. Here we show that BMP2 induces DLX3, a homeodomain protein that activates Runx2 gene transcription. Small interfering RNA knockdown studies in osteoblasts validate that DLX3 is a potent regulator of Runx2. Furthermore in Runx2 null cells, DLX3 forced expression suffices to induce transcription of Runx2, osteocalcin, and alkaline phosphatase genes, thus defining DLX3 as an osteogenic regulator independent of RUNX2. Our studies further show regulation of the Runx2 gene by several homeodomain proteins: MSX2 and CDP/cut repress whereas DLX3 and DLX5 activate endogenous Runx2 expression and promoter activity in non-osseous cells and osteoblasts. These HD proteins exhibit distinct temporal expression profiles during osteoblast differentiation as well as selective association with Runx2 chromatin that is related to Runx2 transcriptional activity and recruitment of RNA polymerase II. Runx2 promoter mutagenesis shows that multiple HD elements control expression of Runx2 in relation to the stages of osteoblast maturation. Our studies establish mechanisms for commitment to the osteogenic lineage directly through BMP2 induction of HD proteins DLX3 and DLX5 that activate Runx2, thus delineating a transcriptional regulatory pathway mediating osteoblast differentiation. We propose that the three homeodomain proteins MSX2, DLX3, and DLX5 provide a key series of molecular switches that regulate expression of Runx2 throughout bone formation.
Giovanni Levi - One of the best experts on this subject based on the ideXlab platform.
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Posterior axis formation requires Dlx5/Dlx6 expression at the neural plate border
PLoS ONE, 2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are essential for anterior neural tube closure, however their role in the formation of the posterior structures has never been described. Here, we show that Dlx5/6 expression is required during vertebrate posterior axis formation. Dlx5 presents a similar expression pattern in neural plate border cells during posterior neurulation of zebrafish and mouse. Dlx5/6-inactivation in the mouse results in a phenotype reminiscent of NTDs characterized by open thoracic and lumbar vertebral arches and failure of epaxial muscle formation at the dorsal midline. The dlx5a/6a zebrafish morphants present posterior NTDs associated with abnormal delamination of neural crest cells showing altered expression of cell adhesion molecules and defects of motoneuronal development. Our findings provide new molecular leads to decipher the mechanisms of vertebrate posterior neurulation and might help to gather a better understanding of human congenital NTDs etiology.
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posterior axis formation requires dlx5 dlx6 expression at the neural plate border
bioRxiv, 2018Co-Authors: Nicolas Narbouxneme, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are essential for anterior neural tube closure, however their role in the formation of the posterior structures has never been described. Here, we show that Dlx5/6 expression is required during vertebrate posterior axis formation. Dlx5 presents a similar expression pattern in neural plate border cells during posterior neurulation of zebrafish and mouse. Dlx5/6-inactivation in the mouse results in a phenotype reminiscent of NTDs characterized by open thoracic and lumbar vertebral arches and failure of epaxial muscle formation at the dorsal midline. The dlx5a/6a zebrafish morphants present posterior NTDs associated with abnormal delamination of neural crest cells showing altered expression of cell adhesion molecules and defects of motoneuronal development. Our findings provide new molecular leads to decipher the mechanisms of vertebrate posterior neurulation and might help to gather a better understanding of human congenital NTDs etiology.
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BMP-Mediated Functional Cooperation between Dlx5;Dlx6 and Msx1;Msx2 during Mammalian Limb Development
2016Co-Authors: Kamal Bouhali, Giulia Garaffo, Paolo Provero, Simonetta Astigiano, Ottavia Barbieri, Mariano F. Caratozzolo, Apollonia Tullo, Luisa Guerrini, Yvan Lallem, Giovanni LeviAbstract:The Dlx and Msx homeodomain transcription factors play important roles in the control of limb development. The combined disruption of Msx1 and Msx2, as well as that of Dlx5 and Dlx6, lead to limb patterning defects with anomalies in digit number and shape. Msx1;Msx2 double mutants are characterized by the loss of derivatives of the anterior limb mesoderm which is not observed in either of the simple mutants. Dlx5;Dlx6 double mutants exhibit hindlimb ectrodactyly. While the morphogenetic action of Msx genes seems to involve the BMP molecules, the mode of action of Dlx genes still remains elusive. Here, examining the limb phenotypes of combined Dlx and Msx mutants we reveal a new Dlx-Msx regulatory loop directly involving BMPs. In Msx1;Dlx5;Dlx6 triple mutant mice (TKO), beside the expected ectrodactyly, we also observe the hallmark morphological anomalies of Msx1;Msx2 double mutants suggesting an epistatic role of Dlx5 and Dlx6 over Msx2. In Msx2;Dlx5;Dlx6 TKO mice we only observe an aggravation of the ectrodactyly defect without changes in the number of the individual components of the limb. Using a combination of qPCR, ChIP and bioinformatic analyses, we identify two Dlx/Msx regulatory pathways: 1) in the anterior limb mesoderm a non-cell autonomous Msx-Dlx regulatory loo
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Dlx5 and Dlx6 expression in the anterior neural fold is essential for patterning the dorsal nasal capsule
Development (Cambridge England), 2011Co-Authors: Yorick Gitton, Kamal Bouhali, Eglantine Heude, Laurence Benouaiche, Christine Vincent, Marina Soulika, Gérard Couly, Giovanni LeviAbstract:Morphogenesis of the vertebrate facial skeleton depends upon inductive interactions between cephalic neural crest cells (CNCCs) and cephalic epithelia. The nasal capsule is a CNCC-derived cartilaginous structure comprising a ventral midline bar (mesethmoid) overlaid by a dorsal capsule (ectethmoid). Although Shh signalling from the anterior-most region of the endoderm (EZ-I) patterns the mesethmoid, the cues involved in ectethmoid induction are still undefined. Here, we show that ectethmoid formation depends upon Dlx5 and Dlx6 expression in a restricted ectodermal territory of the anterior neural folds, which we name NF-ZA. In both chick and mouse neurulas, Dlx5 and Dlx6 expression is mostly restricted to NF-ZA. Simultaneous Dlx5 and Dlx6 inactivation in the mouse precludes ectethmoid formation, while the mesethmoid is still present. Consistently, siRNA-mediated downregulation of Dlx5 and Dlx6 in the cephalic region of the early avian neurula specifically prevents ectethmoid formation, whereas other CNCC-derived structures, including the mesethmoid, are not affected. Similarly, NF-ZA surgical removal in chick neurulas averts ectethmoid development, whereas grafting a supernumerary NF-ZA results in an ectopic ectethmoid. Simultaneous ablation or grafting of both NF-ZA and EZ-I result, respectively, in the absence or duplication of both dorsal and ventral nasal capsule components. The present work shows that early ectodermal and endodermal signals instruct different contingents of CNCCs to form the ectethmoid and the mesethmoid, which then assemble to form a complete nasal capsule.
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induction of apoptosis by fenretinide in tumor cell lines correlates with dlx2 DLX3 and dlx4 gene expression
Oncology Reports, 2003Co-Authors: Nicoletta Ferrari, Giovanni Levi, Laura Paleari, Giulio Lelio Palmisano, Paolo Tammaro, Adriana Albini, Claudio BrigatiAbstract:We investigated a possible relationship between apoptosis induction by fenretinide (4HPR) and the expression of a group of genes thought to be essential in morphogenesis and development, the DLX genes. We analyzed their expression under normal conditions or upon 4HPR stimulation in several tumor cell lines. We show that DLX2, DLX3 and DLX4 were expressed at higher levels in cell lines which where more sensitive to apoptotic induction, whereas DLX 5 and 6 appeared to segregate in a distinct functional compartment. Our data support the notion that DLX2, 3, 4 genes could participate in the control of 4HPR-mediated apoptosis, making them important molecules for the monitoring of therapy efficacy in cancer patients.
Marc Ekker - One of the best experts on this subject based on the ideXlab platform.
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Posterior axis formation requires Dlx5/Dlx6 expression at the neural plate border
PLoS ONE, 2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are essential for anterior neural tube closure, however their role in the formation of the posterior structures has never been described. Here, we show that Dlx5/6 expression is required during vertebrate posterior axis formation. Dlx5 presents a similar expression pattern in neural plate border cells during posterior neurulation of zebrafish and mouse. Dlx5/6-inactivation in the mouse results in a phenotype reminiscent of NTDs characterized by open thoracic and lumbar vertebral arches and failure of epaxial muscle formation at the dorsal midline. The dlx5a/6a zebrafish morphants present posterior NTDs associated with abnormal delamination of neural crest cells showing altered expression of cell adhesion molecules and defects of motoneuronal development. Our findings provide new molecular leads to decipher the mechanisms of vertebrate posterior neurulation and might help to gather a better understanding of human congenital NTDs etiology.
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posterior axis formation requires dlx5 dlx6 expression at the neural plate border
bioRxiv, 2018Co-Authors: Nicolas Narbouxneme, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are essential for anterior neural tube closure, however their role in the formation of the posterior structures has never been described. Here, we show that Dlx5/6 expression is required during vertebrate posterior axis formation. Dlx5 presents a similar expression pattern in neural plate border cells during posterior neurulation of zebrafish and mouse. Dlx5/6-inactivation in the mouse results in a phenotype reminiscent of NTDs characterized by open thoracic and lumbar vertebral arches and failure of epaxial muscle formation at the dorsal midline. The dlx5a/6a zebrafish morphants present posterior NTDs associated with abnormal delamination of neural crest cells showing altered expression of cell adhesion molecules and defects of motoneuronal development. Our findings provide new molecular leads to decipher the mechanisms of vertebrate posterior neurulation and might help to gather a better understanding of human congenital NTDs etiology.
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arcuate nucleus expression of nkx2 1 and dlx and lineages expressing these transcription factors in neuropeptide y proopiomelanocortin and tyrosine hydroxylase neurons in neonatal and adult mice
The Journal of Comparative Neurology, 2009Co-Authors: Cindy L Yee, Marc Ekker, Stewart A Anderson, Yanling Wang, John L R RubensteinAbstract:Despite its small size, the arcuate nucleus of the hypothalamus has a critical role in regulating energy homeostasis. We have begun to define genetic approaches to express genes in specific cell types within the developing arcuate nucleus, to allow precise molecular perturbations of these cells. Furthermore, our analysis aims to contribute to defining the transcriptional networks that regulate the development of function of the arcuate neurons. Here, we define the neuronal cells types within the arcuate that express Nkx2.1 and Dlx homeobox genes. In addition, we used mice expressing Cre recombinase from the Dlx5/6 intergenic enhancer (Dlx5/6i) and from the Nkx2.1 locus to follow the fate of embryonic cells expressing these genes within the arcuate nucleus. We demonstrate that NKX2.1+ cells and their lineages are broadly expressed in arcuate neurons [γ-aminobutyric acid (GABA)+, neuropeptide Y (NPY)+, proopiomelanocortin (POMC)+, tyrosine hydroxylase (TH)+] and glia (tanycytes). On the other hand, DLX+ cells and their lineages mark only GABA+ and TH+ (dopaminergic) neurons, and Dlx1–/– mutants have fewer TH+ neurons. These results have implications for the genetic control of arcuate development and function and for the utility of the Nkx2.1-Cre and Dlx5/6i-Cre mouse lines to alter gene expression in the developing arcuate. J. Comp. Neurol. 517:37–50, 2009. © 2009 Wiley-Liss, Inc.
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ectopic expression of the dlx genes induces glutamic acid decarboxylase and dlx expression
Development, 2002Co-Authors: Thorsten Stuhmer, Marc Ekker, Stewart A Anderson, John L R RubensteinAbstract:The expression of the Dlx homeobox genes is closely associated with neurons that express γ-aminobutyric acid (GABA) in the embryonic rostral forebrain. To test whether the Dlx genes are sufficient to induce some aspects of the phenotype of GABAergic neurons, we adapted the electroporation method to ectopically express DLX proteins in slice cultures of the mouse embryonic cerebral cortex. This approach showed that ectopic expression of Dlx2 and Dlx5 induced the expression of glutamic acid decarboxylases (GADs), the enzymes that synthesize GABA. We also used this method to show cross-regulation between different Dlx family members. We find that Dlx2 can induce Dlx5 expression, and that Dlx1, Dlx2 and Dlx5 can induce expression from a Dlx5/6-lacZ enhancer/”reporter construct.
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a highly conserved enhancer in the dlx5 dlx6 intergenic region is the site of cross regulatory interactions between dlx genes in the embryonic forebrain
The Journal of Neuroscience, 2000Co-Authors: Ted Zerucha, Marc Ekker, John L R Rubenstein, Thorsten Stuhmer, Gary Hatch, Byung Keon Park, Qiaoming Long, Adrianna Gambarotta, Joshua R SchultzAbstract:Four Dlx homeobox genes, Dlx1, Dlx2, Dlx5, and Dlx6 are expressed in the same primordia of the mouse forebrain with temporally overlapping patterns. The four genes are organized as two tail-to-tail pairs, Dlx1/Dlx2 and Dlx5/Dlx6, a genomic arrangement conserved in distantly related vertebrates like zebrafish. The Dlx5/Dlx6 intergenic region contains two sequences of a few hundred base pairs, remarkably well conserved between mouse and zebrafish. Reporter transgenes containing these two sequences are expressed in the forebrain of transgenic mice and zebrafish with patterns highly similar to endogenous Dlx5 and Dlx6 expression. The activity of the transgene is drastically reduced in mouse mutants lacking both Dlx1 and Dlx2, consistent with the decrease in endogenous Dlx5 and Dlx6 expression. These results suggest that cross-regulation by Dlx proteins, mediated by the intergenic sequences, is essential for Dlx5 and Dlx6 expression in the forebrain. This hypothesis is supported by cotransfection and DNA-protein binding experiments. We propose that the Dlx genes are part of a highly conserved developmental pathway that regulates forebrain development.
Eglantine Heude - One of the best experts on this subject based on the ideXlab platform.
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dlx5 and dlx6 expression in gabaergic neurons controls behavior metabolism healthy aging and lifespan
Aging (Albany NY), 2019Co-Authors: Camille De Lombares, Eglantine Heude, Gladys Alfama, Anastasia Fontaine, Rim Hassouna, Cecile Vernochet, Fabrice De Chaumont, Christophe Olivomarin, Elodie Ey, Sebastien ParnaudeauAbstract:: Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development, Dlx5/6 play a role in the differentiation of certain GABAergic subclasses. Here we address the question of the functional role of Dlx5/6 in the mature central nervous system. First, we demonstrate that Dlx5 and Dlx6 are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyze VgatΔDlx5-6 mice in which Dlx5 and Dlx6 are simultaneously inactivated in all GABAergic interneurons. VgatΔDlx5-6 mice present a behavioral pattern suggesting reduction of anxiety-like behavior and obsessive-compulsive activities, and a lower interest in nest building. Twenty-month-old VgatΔDlx5-6 animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, both VgatΔDlx5-6/+ and VgatΔDlx5-6 mice present a 33% longer median survival. Hallmarks of biological aging such as motility, adiposity and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate healthspan and lifespan through Dlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.
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dlx5 and dlx6 expression in gabaergic neurons controls behavior metabolism healthy aging and lifespan
bioRxiv, 2019Co-Authors: Camille De Lombares, Eglantine Heude, Gladys Alfama, Anastasia Fontaine, Rim Hassouna, Cecile Vernochet, Fabrice De Chaumont, Christophe Olivomarin, Elodie Ey, Sebastien ParnaudeauAbstract:Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development Dlx5/6 are important for the differentiation of Parvalbumin (Pvalb)-expressing neurons. Perinatal lethality of homozygous mice in which Dlx5/6 have been constitutively deleted has, so far, hindered the study of the function of these genes in adult neurons. We first show that Dlx5 and Dlx6 are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyse Vgat{Delta}Dlx5-6 mice in which Dlx5 and Dlx6 are simultaneously inactivated in all GABAergic interneurons. Vgat{Delta}Dlx5-6 mice present a behavioral pattern suggesting reduction of anxiety and obsessive-compulsive activities. They rapidly access and spend more time in the central region of an open field, bury few marbles in the marble burying test and show little interest in nest building. Male and female 20-month-old Vgat{Delta}Dlx5-6 animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, both Vgat{Delta}Dlx5-6/+ and Vgat{Delta}Dlx5-6 mice present a 33% longer median survival than their control littermates. Hallmarks of biological aging such as motility, adipose deposition and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate mammalian healthspan and lifespan through Dlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.nnSIGNIFICANCE STATEMENTDlx5 and Dlx6 are transcription factors controlling several developmental processes, including GABAergic neuronal migration and differentiation. To study their function in adult brain, we selectively inactivated both genes in GABAergic interneurons (Vgat{Delta}Dlx5-6 mice). Mutant mice have reduced anxiety-like and obsessive-compulsive behaviors. Interestingly, Vgat{Delta}Dlx5-6 mice have a 25% body weight reduction and about 70% less white and brown adipose tissue; their general health status is excellent. Vgat{Delta}Dlx5-6 mice have a median survival about 33% longer than their control littermates and hallmarks of biological aging are improved. Dlx5/6-dependent regulations in GABAergic neurons could be an entry point to understand how the brain determines the psychophysiological status of the body and, ultimately, longevity and healthy aging.
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Posterior axis formation requires Dlx5/Dlx6 expression at the neural plate border
PLoS ONE, 2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are essential for anterior neural tube closure, however their role in the formation of the posterior structures has never been described. Here, we show that Dlx5/6 expression is required during vertebrate posterior axis formation. Dlx5 presents a similar expression pattern in neural plate border cells during posterior neurulation of zebrafish and mouse. Dlx5/6-inactivation in the mouse results in a phenotype reminiscent of NTDs characterized by open thoracic and lumbar vertebral arches and failure of epaxial muscle formation at the dorsal midline. The dlx5a/6a zebrafish morphants present posterior NTDs associated with abnormal delamination of neural crest cells showing altered expression of cell adhesion molecules and defects of motoneuronal development. Our findings provide new molecular leads to decipher the mechanisms of vertebrate posterior neurulation and might help to gather a better understanding of human congenital NTDs etiology.
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posterior axis formation requires dlx5 dlx6 expression at the neural plate border
bioRxiv, 2018Co-Authors: Nicolas Narbouxneme, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:Neural tube defects (NTDs), one of the most common birth defects in human, present a multifactorial etiology with a poorly defined genetic component. The Dlx5 and Dlx6 bigenic cluster encodes two evolutionary conserved homeodomain transcription factors, which are necessary for proper vertebrate development. It has been shown that Dlx5/6 genes are essential for anterior neural tube closure, however their role in the formation of the posterior structures has never been described. Here, we show that Dlx5/6 expression is required during vertebrate posterior axis formation. Dlx5 presents a similar expression pattern in neural plate border cells during posterior neurulation of zebrafish and mouse. Dlx5/6-inactivation in the mouse results in a phenotype reminiscent of NTDs characterized by open thoracic and lumbar vertebral arches and failure of epaxial muscle formation at the dorsal midline. The dlx5a/6a zebrafish morphants present posterior NTDs associated with abnormal delamination of neural crest cells showing altered expression of cell adhesion molecules and defects of motoneuronal development. Our findings provide new molecular leads to decipher the mechanisms of vertebrate posterior neurulation and might help to gather a better understanding of human congenital NTDs etiology.
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Dlx5 and Dlx6 expression in the anterior neural fold is essential for patterning the dorsal nasal capsule
Development (Cambridge England), 2011Co-Authors: Yorick Gitton, Kamal Bouhali, Eglantine Heude, Laurence Benouaiche, Christine Vincent, Marina Soulika, Gérard Couly, Giovanni LeviAbstract:Morphogenesis of the vertebrate facial skeleton depends upon inductive interactions between cephalic neural crest cells (CNCCs) and cephalic epithelia. The nasal capsule is a CNCC-derived cartilaginous structure comprising a ventral midline bar (mesethmoid) overlaid by a dorsal capsule (ectethmoid). Although Shh signalling from the anterior-most region of the endoderm (EZ-I) patterns the mesethmoid, the cues involved in ectethmoid induction are still undefined. Here, we show that ectethmoid formation depends upon Dlx5 and Dlx6 expression in a restricted ectodermal territory of the anterior neural folds, which we name NF-ZA. In both chick and mouse neurulas, Dlx5 and Dlx6 expression is mostly restricted to NF-ZA. Simultaneous Dlx5 and Dlx6 inactivation in the mouse precludes ectethmoid formation, while the mesethmoid is still present. Consistently, siRNA-mediated downregulation of Dlx5 and Dlx6 in the cephalic region of the early avian neurula specifically prevents ectethmoid formation, whereas other CNCC-derived structures, including the mesethmoid, are not affected. Similarly, NF-ZA surgical removal in chick neurulas averts ectethmoid development, whereas grafting a supernumerary NF-ZA results in an ectopic ectethmoid. Simultaneous ablation or grafting of both NF-ZA and EZ-I result, respectively, in the absence or duplication of both dorsal and ventral nasal capsule components. The present work shows that early ectodermal and endodermal signals instruct different contingents of CNCCs to form the ectethmoid and the mesethmoid, which then assemble to form a complete nasal capsule.