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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.
Marc Ekker - One of the best experts on this subject based on the ideXlab platform.
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Increased Sociability in Mice Lacking Intergenic Dlx Enhancers
'Frontiers Media SA', 2021Co-Authors: Siavash Fazel Darbandi, Gary Hatch, Crystal Esau, Cindy Lesage-pelletier, Simon Monis, Luc Poitras, Sofia Perin, Marc EkkerAbstract:The Dlx homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six Dlx genes organized into three convergently transcribed bigene clusters (Dlx1/2, Dlx3/4, and DLX5/6) with cis-regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the Dlx1/2 and DLX5/6 locus, respectively, are active in the developing forebrain. I56i is also a binding site for GTF2I, a transcription factor whose function is associated with increased sociability and Williams–Beuren syndrome. In determining the regulatory roles of these CREs on forebrain development, we have generated mutant mouse-lines where Dlx forebrain intergenic enhancers have been deleted (I56i(–/–), I12b(–/–)). Loss of Dlx intergenic enhancers impairs expression of Dlx genes as well as some of their downstream targets or associated genes including Gad2 and Evf2. The loss of the I56i enhancer resulted in a transient decrease in GABA+ cells in the developing forebrain. The intergenic enhancer mutants also demonstrate increased sociability and learning deficits in a fear conditioning test. Characterizing mice with mutated Dlx intergenic enhancers will help us to further enhance our understanding of the role of these Dlx genes in forebrain development
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Expression of dlx genes in the normal and regenerating brain of adult zebrafish.
'Public Library of Science (PLoS)', 2020Co-Authors: Hellen Weinschutz Mendes, Mariam Taktek, Thomas Duret, Marc EkkerAbstract:Dysfunctions in the GABAergic system lead to various pathological conditions and impaired inhibitory function is one of the causes behind neuropathies characterized by neuronal hyper excitability. The Dlx homeobox genes are involved in the development of nervous system, neural crest, branchial arches and developing appendages. Dlx genes also take part in neuronal migration and differentiation during development, more precisely, in the migration and differentiation of GABAergic neurons. Functional analysis of dlx genes has mainly been carried out in developing zebrafish embryos and larvae, however information regarding the expression and roles of these genes in the adult zebrafish brain is still lacking. The extensive neurogenesis that takes place in the adult zebrafish brain, makes them a good model for the visualization of mechanisms involving dlx genes during adulthood in physiological conditions and during regeneration of the nervous system. We have identified the adult brain regions where transcripts of dlx1a, dlx2a, DLX5a and dlx6a genes are normally found and have confirmed that within telencephalic domains, there is high overlapping expression of the four dlx paralogs with a marker for GABAergic neurons. Co-localization analyses carried with the Tg(dlx6a-1.4kbDLX5a/dlx6a:GFP) reporter line have also shown that in some areas of the diencephalon, cells expressing the DLX5a/6a bigene may have a neural stem cell identity. Furthermore, investigations in a response to stab wound lesions, have demonstrated a possible participation of the DLX5a/6a bigene, most likely of DLX5a, during regeneration of the adult zebrafish brain. These observations suggest a possible participation of dlx-expressing cells during brain regeneration in adult zebrafish and also provide information on the role of dlx genes under normal physiological conditions in adults
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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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Early phenotype of DLX5/6-inactivated zebrafish and mouse.
2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:(A-B) Phenotype of wild type (WT) and DLX5a/6a morphant zebrafish at 48 hpf (n>750 for each condition). (C-D) Phenotype of WT and DLX5/6-/- mutant mice at E11.5 (n = 6 for each condition). Inactivation of DLX5/6 in zebrafish and mouse leads to early defect of posterior axis development characterized by curly-shaped tail phenotype in both models (B, D, white arrowheads). In DLX5/6-/- embryos, the caudal phenotype is associated with defect of brain formation (D, blue arrowhead). Scale bar in B for A-B 100 μm, for C-D 1000 μm.
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DLX5 expression analysis during zebrafish and mouse posterior neurulation.
2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:(A-D) Whole-mount in situ hybridization for DLX5a and DLX5; (A, C) dorsal and (B, D) lateral views of the posterior axis of 15.5 hpf and 16 hpf zebrafish (A-B) and E8.25 and E9.5 mouse embryos (C-D). (E-H) In situ hybridization for DLX5 on coronal cryosections at the levels indicated by the dashed lines in (C, D and S1 Fig). In zebrafish embryos, DLX5a transcripts are detected in NPB cells along neural keel at 15.5 hpf and at the dorsal midline at 16 hpf (A-B, black arrowheads). During mouse posterior neurulation, DLX5 is expressed in NPB cells surrounding the posterior neuropore and along the dorsal midline of the neural tube after neural tube closure (C-H, black arrowheads). In both species, DLX5 is also detected in the ventral ectodermal ridge of the tail bud and at the cloacal level (grey and blue arrowheads respectively in B, D) (n>10 for each conditions). Abbreviations: nc, notochord; nk, neural keel; np, neural plate; nt, neural tube; pnp, posterior neuropore; psm, presomitic mesoderm; sm, somitic mesoderm; tb, tail bud; ys, yolk sac. Scale bar in H for A, H 50 μm, for B, E-G 75 μm, for C 150 μm, for D 200 μm.
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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Early phenotype of DLX5/6-inactivated zebrafish and mouse.
2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:(A-B) Phenotype of wild type (WT) and DLX5a/6a morphant zebrafish at 48 hpf (n>750 for each condition). (C-D) Phenotype of WT and DLX5/6-/- mutant mice at E11.5 (n = 6 for each condition). Inactivation of DLX5/6 in zebrafish and mouse leads to early defect of posterior axis development characterized by curly-shaped tail phenotype in both models (B, D, white arrowheads). In DLX5/6-/- embryos, the caudal phenotype is associated with defect of brain formation (D, blue arrowhead). Scale bar in B for A-B 100 μm, for C-D 1000 μm.
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DLX5 expression analysis during zebrafish and mouse posterior neurulation.
2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:(A-D) Whole-mount in situ hybridization for DLX5a and DLX5; (A, C) dorsal and (B, D) lateral views of the posterior axis of 15.5 hpf and 16 hpf zebrafish (A-B) and E8.25 and E9.5 mouse embryos (C-D). (E-H) In situ hybridization for DLX5 on coronal cryosections at the levels indicated by the dashed lines in (C, D and S1 Fig). In zebrafish embryos, DLX5a transcripts are detected in NPB cells along neural keel at 15.5 hpf and at the dorsal midline at 16 hpf (A-B, black arrowheads). During mouse posterior neurulation, DLX5 is expressed in NPB cells surrounding the posterior neuropore and along the dorsal midline of the neural tube after neural tube closure (C-H, black arrowheads). In both species, DLX5 is also detected in the ventral ectodermal ridge of the tail bud and at the cloacal level (grey and blue arrowheads respectively in B, D) (n>10 for each conditions). Abbreviations: nc, notochord; nk, neural keel; np, neural plate; nt, neural tube; pnp, posterior neuropore; psm, presomitic mesoderm; sm, somitic mesoderm; tb, tail bud; ys, yolk sac. Scale bar in H for A, H 50 μm, for B, E-G 75 μm, for C 150 μm, for D 200 μm.
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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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posterior neural tube closure depends on 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 neural tube has never been described. Here, we show that DLX5/6 expression is required during vertebrate posterior neural tube closure. DLX5 presents a similar expression pattern in neural plate border cells during zebrafish and mouse posterior neurulation. DLX5/6-inactivation in 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. Similarly, DLX5a/6a zebrafish morphants show defects of posterior neural tube closure accompanied by aberrant delamination of neural crest cells with altered expression of cell adhesion molecules and defects of motoneuron formation. Our findings provide new molecular leads to decipher the mechanisms involved during vertebrate posterior neurulation for a better understanding of the etiology of human congenital NTDs and other midline field defects.
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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Early phenotype of DLX5/6-inactivated zebrafish and mouse.
2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:(A-B) Phenotype of wild type (WT) and DLX5a/6a morphant zebrafish at 48 hpf (n>750 for each condition). (C-D) Phenotype of WT and DLX5/6-/- mutant mice at E11.5 (n = 6 for each condition). Inactivation of DLX5/6 in zebrafish and mouse leads to early defect of posterior axis development characterized by curly-shaped tail phenotype in both models (B, D, white arrowheads). In DLX5/6-/- embryos, the caudal phenotype is associated with defect of brain formation (D, blue arrowhead). Scale bar in B for A-B 100 μm, for C-D 1000 μm.
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DLX5 expression analysis during zebrafish and mouse posterior neurulation.
2019Co-Authors: Nicolas Narboux-nême, Giovanni Levi, Marc Ekker, Eglantine HeudeAbstract:(A-D) Whole-mount in situ hybridization for DLX5a and DLX5; (A, C) dorsal and (B, D) lateral views of the posterior axis of 15.5 hpf and 16 hpf zebrafish (A-B) and E8.25 and E9.5 mouse embryos (C-D). (E-H) In situ hybridization for DLX5 on coronal cryosections at the levels indicated by the dashed lines in (C, D and S1 Fig). In zebrafish embryos, DLX5a transcripts are detected in NPB cells along neural keel at 15.5 hpf and at the dorsal midline at 16 hpf (A-B, black arrowheads). During mouse posterior neurulation, DLX5 is expressed in NPB cells surrounding the posterior neuropore and along the dorsal midline of the neural tube after neural tube closure (C-H, black arrowheads). In both species, DLX5 is also detected in the ventral ectodermal ridge of the tail bud and at the cloacal level (grey and blue arrowheads respectively in B, D) (n>10 for each conditions). Abbreviations: nc, notochord; nk, neural keel; np, neural plate; nt, neural tube; pnp, posterior neuropore; psm, presomitic mesoderm; sm, somitic mesoderm; tb, tail bud; ys, yolk sac. Scale bar in H for A, H 50 μm, for B, E-G 75 μm, for C 150 μm, for D 200 μm.
Junichi Iwata - One of the best experts on this subject based on the ideXlab platform.
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Msx1 and DLX5 function synergistically to regulate frontal bone development.
genesis, 2010Co-Authors: Il Hyuk Chung, Jun Han, Junichi IwataAbstract:The Msx and Dlx families of homeobox proteins are important regulators for embryogenesis. Loss of Msx1 in mice results in multiple developmental defects including craniofacial malformations. Although DLX5 is widely expressed during embryonic development, targeted null mutation of DLX5 mainly affects the development of craniofacial bones. Msx1 and DLX5 show overlapping expression patterns during frontal bone development. To investigate the functional significance of Msx1/DLX5 interaction in regulating frontal bone development, we generated Msx1 and DLX5 double null mutant mice. In Msx1−/−;DLX5−/− mice, the frontal bones defect was more severe than that of either Msx1−/− or DLX5−/− mice. This aggravated frontal bone defect suggests that Msx1 and DLX5 function synergistically to regulate osteogenesis. This synergistic effect of Msx1 and DLX5 on the frontal bone represents a tissue specific mode of interaction of the Msx and Dlx genes. Furthermore, DLX5 requires Msx1 for its expression in the context of frontal bone development. Our study shows that Msx1/DLX5 interaction is crucial for osteogenic induction during frontal bone development. genesis 48:645–655, 2010. © 2010 Wiley-Liss, Inc.
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msx1 and DLX5 function synergistically to regulate frontal bone development
Genesis, 2010Co-Authors: Il Hyuk Chung, Jun Han, Junichi IwataAbstract:The Msx and Dlx families of homeobox proteins are important regulators for embryogenesis. Loss of Msx1 in mice results in multiple developmental defects including craniofacial malformations. Although DLX5 is widely expressed during embryonic development, targeted null mutation of DLX5 mainly affects the development of craniofacial bones. Msx1 and DLX5 show overlapping expression patterns during frontal bone development. To investigate the functional significance of Msx1/DLX5 interaction in regulating frontal bone development, we generated Msx1 and DLX5 double null mutant mice. In Msx1(-/-) ;DLX5(-/-) mice, the frontal bones defect was more severe than that of either Msx1(-/-) or DLX5(-/-) mice. This aggravated frontal bone defect suggests that Msx1 and DLX5 function synergistically to regulate osteogenesis. This synergistic effect of Msx1 and DLX5 on the frontal bone represents a tissue specific mode of interaction of the Msx and Dlx genes. Furthermore, DLX5 requires Msx1 for its expression in the context of frontal bone development. Our study shows that Msx1/DLX5 interaction is crucial for osteogenic induction during frontal bone development.