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Juha Partanen - One of the best experts on this subject based on the ideXlab platform.
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Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei.
Development (Cambridge England), 2015Co-Authors: Laura Lahti, Laura Tikker, Marjo Salminen, Maarja Haugas, Mikko Airavaara, Merja H. Voutilainen, Jenni E. Anttila, Suman Kumar, Caisa Inkinen, Juha PartanenAbstract:Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral Rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.
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distinct developmental origins and regulatory mechanisms for gabaergic neurons associated with dopaminergic nuclei in the ventral mesodiencephalic region
Development, 2012Co-Authors: Kaia Achim, Laura Lahti, Paula Peltopuro, Marjo Salminen, Juha PartanenAbstract:GABAergic neurons in the ventral mesodiencephalic region are highly important for the function of dopaminergic pathways that regulate multiple aspects of behavior. However, development of these neurons is poorly understood. We recently showed that molecular regulation of differentiation of the GABAergic neurons associated with the dopaminergic nuclei in the ventral midbrain (VTA and SNpr) is distinct from the rest of midbrain, but the reason for this difference remained elusive. Here, we have analyzed the developmental origin of the VTA and SNpr GABAergic neurons by genetic fate mapping. We demonstrate that the majority of these GABAergic neurons originate outside the midbrain, from Rhombomere 1, and move into the ventral midbrain only as postmitotic neuronal precursors. We further show that Gata2, Gata3 and Tal1 define a subpopulation of GABAergic precursors in ventral Rhombomere 1. A failure in GABAergic neuron differentiation in this region correlates with loss of VTA and SNpr GABAergic neurons in Tal1 mutant mice. In contrast to midbrain, GABAergic neurons of the anterior SNpr in the diencephalon are not derived from the Rhombomere 1. These results suggest unique migratory pathways for the precursors of important GABAergic neuron subpopulations, and provide the basis for understanding diversity within midbrain GABAergic neurons.
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beta-Catenin Regulates Intercellular Signalling Networks and Cell-Type Specific Transcription in the Developing Mouse Midbrain-Rhombomere 1 Region
PloS one, 2010Co-Authors: Dmitri Chilov, Natalia Sinjushina, Jonna Saarimäki-vire, Makoto Mark Taketo, Juha PartanenAbstract:β-catenin is a multifunctional protein involved in both signalling by secreted factors of Wnt family and regulation of the cellular architecture. We show that β-catenin stabilization in mouse midbrain-Rhombomere1 region leads to robust up-regulation of several Wnt signalling target genes, including Fgf8. Suggestive of direct transcriptional regulation of the Fgf8 gene, β-catenin stabilization resulted in Fgf8 up-regulation also in other tissues, specifically in the ventral limb ectoderm. Interestingly, stabilization of β-catenin rapidly caused down-regulation of the expression of Wnt1 itself, suggesting a negative feedback loop. The changes in signal molecule expression were concomitant with deregulation of anterior-posterior and dorso-ventral patterning. The transcriptional regulatory functions of β-catenin were confirmed by β-catenin loss-of-function experiments. Temporally controlled inactivation of β-catenin revealed a cell-autonomous role for β-catenin in the maintenance of cell-type specific gene expression in the progenitors of midbrain dopaminergic neurons. These results highlight the role of β-catenin in establishment of neuroectodermal signalling centers, promoting region-specific gene expression and regulation of cell fate determination.
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Gata2 is a tissue-specific post-mitotic selector gene for midbrain GABAergic neurons.
Development (Cambridge England), 2008Co-Authors: Kaia Kala, Wolfgang Wurst, Marjo Salminen, Maarja Haugas, Kersti Lilleväli, Jordi Guimera, Juha PartanenAbstract:Midbrain GABAergic neurons control several aspects of behavior, but regulation of their development and diversity is poorly understood. Here, we further refine the midbrain regions active in GABAergic neurogenesis and show their correlation with the expression of the transcription factor Gata2. Using tissue-specific inactivation and ectopic expression, we show that Gata2 regulates GABAergic neuron development in the mouse midbrain, but not in Rhombomere 1, where it is needed in the serotonergic lineage. Without Gata2, all the precursors in the embryonic midbrain fail to activate GABAergic neuron-specific gene expression and instead switch to a glutamatergic phenotype. Surprisingly, this fate switch is also observed throughout the neonatal midbrain, except for the GABAergic neurons located in the ventral dopaminergic nuclei, suggesting a distinct developmental pathway for these neurons. These studies identify Gata2 as an essential post-mitotic selector gene of the GABAergic neurotransmitter identity and demonstrate developmental heterogeneity of GABAergic neurons in the midbrain.
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Analysis of the midbrain-hindbrain boundary cell fate using a boundary cell-specific Cre-mouse strain
Genesis (New York N.Y. : 2000), 2008Co-Authors: Kaia Kala, Tomi Jukkola, Illar Pata, Juha PartanenAbstract:Summary: We describe here a transgenic mouse lineMHB-Cre, which expresses Cre recombinase in a groupof cells at the midbrain–hindbrain boundary. Using thismouse line, we studied the contribution of the boundarycells to distinct brain areas during development. Initially,the MHB-Cre expression coincides with that of Cdh22and p21 around the Otx2 expression border in a narrowpopulation of cells with reduced proliferative activity.Consistent with their location on both sides of the Otx2expression border, the Cre expressing boundary cellscontribute both to midbrain as well as hindbrain. How-ever, the majority of recombinant cells remain close tothe mid- and hindbrain border, suggesting very limitedcell mixing within these brain compartments during de-velopment. Interestingly, dorsocaudally oriented fibersof the midbrain dopaminergic neurons follow the pathmarked by the boundary cells. genesis 46:29–36, 2008. VV C 2008 Wiley-Liss, Inc. Key words: cre recombinase; midbrain; Rhombomere 1;boundary; fate mapping
Richard Jt Wingate - One of the best experts on this subject based on the ideXlab platform.
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Specification of Granule Cells and Purkinje Cells
Handbook of the Cerebellum and Cerebellar Disorders, 2019Co-Authors: Thomas Butts, Leigh Wilson, Victoria Rook, Tristan Jan Dacles Varela, Richard Jt WingateAbstract:Granule cells and Purkinje cells are the major populations of neurons in the cerebellum. Their specification depends on a combination of regional identity and spatiotemporal cues. These are conferred by patterning systems in the early embryo that determine anteroposterior and dorsoventral positional coordinates and an age-dependent signal (or signals) whose nature is obscure. While a number of important questions remain about the nature of cerebellar progenitor pools and their precise boundaries, a variety of fate-mapping and genetic approaches have indicated that both granule cells and Purkinje cells arise from different dorsoventral domains within hindbrain Rhombomere 1. Unusually, granule cell precursors undergo a subsequent transit amplification stage regulated by Purkinje cell signals, within a transient superficial germinal layer. Recent evolutionary insights suggest that this phase of Sonic hedgehogdependent transit amplification is only found in amniotes. Evolutionarily, since secondary proliferation arose independently of granule cell specification, it is likely to be an adaptation purely for postspecification regulation of granule cell numbers.
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Independently specified Atoh1 domains define novel developmental compartments in Rhombomere 1.
Development (Cambridge England), 2013Co-Authors: Mary J Green, Anna Myat, Brian A. Emmenegger, Robert J. Wechsler-reya, Leigh Wilson, Richard Jt WingateAbstract:The rhombic lip gives rise to neuronal populations that contribute to cerebellar, proprioceptive and interoceptive networks. Cell production depends on the expression of the basic helix-loop-helix (bHLH) transcription factor Atoh1. In Rhombomere 1, Atoh1-positive cells give rise to both cerebellar neurons and extra-cerebellar nuclei in ventral hindbrain. The origin of this cellular diversity has previously been attributed to temporal signals rather than spatial patterning. Here, we show that in both chick and mouse the cerebellar Atoh1 precursor pool is partitioned into initially cryptic spatial domains that reflect the activity of two different organisers: an isthmic Atoh1 domain, which gives rise to isthmic nuclei, and the rhombic lip, which generates deep cerebellar nuclei and granule cells. We use a combination of in vitro explant culture, genetic fate mapping and gene overexpression and knockdown to explore the role of isthmic signalling in patterning these domains. We show that an FGF-dependent isthmic Atoh1 domain is the origin of distinct populations of Lhx9-positive neurons in the extra-cerebellar isthmic nuclei. In the cerebellum, ectopic FGF induces proliferation while blockade reduces the length of the cerebellar rhombic lip. FGF signalling is not required for the specification of cerebellar cell types from the rhombic lip and its upregulation inhibits their production. This suggests that although the isthmus regulates the size of the cerebellar anlage, the downregulation of isthmic FGF signals is required for induction of rhombic lip-derived cerebellar neurons.
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Temporal identity transition in the avian cerebellar rhombic lip
Developmental biology, 2006Co-Authors: Leigh Wilson, Richard Jt WingateAbstract:The rhombic lip is a discrete strip of neuroepithelium bordering the roofplate of the fourth ventricle, which gives rise to a defined sequence of migratory neuronal derivatives. In Rhombomere 1 of the chick, early born cells give rise to post-mitotic hindbrain nuclei, while later derivatives comprise of cerebellar granule cell precursors, a unique proliferative, migratory precursor population that forms the external granule cell layer. We have examined the temporal specification of these two populations using a heterochronic grafting strategy, in ovo. When transplanted into younger neural tube, rhombic lip cells maintain their characteristic molecular markers and migrate into the hindbrain. Granule cell precursor derivatives of late grafts are, in addition, able to exploit neural crest streams to populate the branchial arches. Within the neural tube, derivatives of early and late rhombic lip progenitors display patterns of migration and process extension, characterised by specific trajectories and targets, which are consistent with their temporal origin. However, the normal temporal progression of cell production is disrupted in grafted progenitors: transplanted early rhombic lip fails to subsequently produce granule cell precursors. This indicates that, while the behaviour of derivatives is intrinsically specified at the rhombic lip, the orderly temporal transition in cell type production is dependent on extrinsic cues present only in the later embryo.
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Segmental identity and cerebellar granule cell induction in Rhombomere 1
BMC Biology, 2004Co-Authors: Mark Eddison, Leah Toole, Esther Bell, Richard Jt WingateAbstract:Background Cerebellar granule cell precursors are specifically generated within the hindbrain segment, Rhombomere 1, which is bounded rostrally by the midbrain/hindbrain isthmus and caudally by the boundary of the Hoxa2 expression domain. While graded signals from the isthmus have a demonstrable patterning role within this region, the significance of segmental identity for neuronal specification within Rhombomere 1 is unexplored. We examined the response of granule cell precursors to the overexpression of Hoxa2 , which normally determines patterns of development specific to the hindbrain. How much does the development of the cerebellum, a midbrain/hindbrain structure, reflect its neuromeric origin as a hindbrain segment? Results We show that a Gbx2 -positive, Otx2 -/ Hoxa2 -negative territory corresponding to Rhombomere 1 forms prior to an identifiable isthmic organiser. Early global overexpression of Hoxa2 at embryonic day 0 has no effect on the expression of isthmic signalling molecules or the allocation of Rhombomere 1 territory, but selectively results in the loss of granule cell markers at embryonic day 6 and the depletion of cell bodies from the external granule cell layer. By comparison the trochlear nucleus and locus coeruleus form normally in ventral Rhombomere 1 under these conditions. Microsurgery, coupled with electroporation, to target Hoxa2 overexpression to rhombic lip precursors, reveals a profound, autonomous respecification of migration. Rhombic lip derivatives, normally destined to occupy the external granule cell layer, violate the cerebellar boundary to form a ventrolateral nucleus in a position comparable to that occupied by rhombic lip derived neurons in Rhombomere 2. Conclusions Different overexpression strategies reveal that the recognition of migration cues by granule cell precursors is dependent on their identity as Rhombomere 1 derivatives. Segmental patterning cues operate autonomously within the rhombic lip precursor pool. By contrast, a subset of coextensive nuclei is refractory to ectopic Hoxa2 and is presumably induced solely by isthmic organiser activity. Thus, graded (isthmic) and segmental mechanisms may operate exclusively of one another in the specification of different neuronal populations within Rhombomere 1. The early designation of an Otx2 -negative, Hoxa2 -negative region, prior to the appearance of the isthmic organiser, is a key initial step in the specification of the cerebellum.
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The migration of cerebellar rhombic lip derivatives.
Development (Cambridge England), 2002Co-Authors: Jonathan D Gilthorpe, Alain Chedotal, Andrew Lumsden, Elli-kalliopi Papantoniou, Richard Jt WingateAbstract:We have used cell labelling, co-culture and time-lapse confocal microscopy to investigate tangential neuronal migration from the rhombic lip. Cerebellar rhombic lip derivatives demonstrate a temporal organisation with respect to their morphology and response to migration cues. Early born cells, which migrate into ventral Rhombomere 1, have a single long leading process that turns at the midline and becomes an axon. Later born granule cell precursors also migrate ventrally but halt at the lateral edge of the cerebellum, correlating with a loss of sensitivity to netrin 1 and expression of Robo2. The rhombic lip and ventral midline express Slit2 and both early and late migrants are repelled by sources of Slit2 in co-culture. These studies reveal an intimate relationship between birthdate, response to migration cues and neuronal fate in an identified population of migratory cells. The use of axons in navigating cell movement suggests that tangential migration is an elaboration of the normal process of axon extension.
Ivor Mason - One of the best experts on this subject based on the ideXlab platform.
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Fibroblast growth factor (FGF) gene expression in the developing cerebellum suggests multiple roles for FGF signaling during cerebellar morphogenesis and development.
Developmental dynamics : an official publication of the American Association of Anatomists, 2009Co-Authors: Yuichiro Yaguchi, Ivor Mason, Mohi Ahmed, Mary Berry, M. Albert BassonAbstract:The cerebellum is derived from the anterior-most segment of the embryonic hindbrain, Rhombomere 1 (r1). Previous studies have shown that the early development and patterning of r1 requires fibroblast growth factor (FGF) signaling. However, many of the developmental processes that shape cerebellar morphogenesis take place later in embryonic development and during the first 2 weeks of postnatal life in the mouse. Here, we present a more comprehensive analysis of the expression patterns of genes encoding FGF receptors and secreted FGF ligands during these later stages of cerebellar development. We show that these genes are expressed in multiple cell types in the developing cerebellum, in an astonishing array of distinct patterns. These data suggest that FGF signaling functions throughout cerebellar development to regulate many processes that shape the formation of a functional cerebellum. Developmental Dynamics, 2009. © 2009 Wiley-Liss, Inc.
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Specific regions within the embryonic midbrain and cerebellum require different levels of FGF signaling during development
Development (Cambridge England), 2008Co-Authors: M. Albert Basson, Salvador Martinez, Alexandra L. Joyner, Ivor Mason, Diego Echevarria, Christina P. Ahn, Anamaria Sudarov, Gail R MartinAbstract:Prospective midbrain and cerebellum formation are coordinated by FGF ligands produced by the isthmic organizer. Previous studies have suggested that midbrain and cerebellum development require different levels of FGF signaling. However, little is known about the extent to which specific regions within these two parts of the brain differ in their requirement for FGF signaling during embryogenesis. Here, we have explored the effects of inhibiting FGF signaling within the embryonic mouse midbrain (mesencephalon) and cerebellum (Rhombomere 1) by misexpressing sprouty2 (Spry2) from an early stage. We show that such Spry2 misexpression moderately reduces FGF signaling, and that this reduction causes cell death in the anterior mesencephalon, the region furthest from the source of FGF ligands. Interestingly, the remaining mesencephalon cells develop into anterior midbrain, indicating that a low level of FGF signaling is sufficient to promote only anterior midbrain development. Spry2 misexpression also affects development of the vermis, the part of the cerebellum that spans the midline. We found that, whereas misexpression of Spry2 alone caused loss of the anterior vermis, reducing FGF signaling further, by decreasing Fgf8 gene dose, resulted in loss of the entire vermis. Our data suggest that cell death is not responsible for vermis loss, but rather that it fails to develop because reducing FGF signaling perturbs the balance between vermis and roof plate development in Rhombomere 1. We suggest a molecular explanation for this phenomenon by providing evidence that FGF signaling functions to inhibit the BMP signaling that promotes roof plate development.
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Sustained interactive Wnt and FGF signaling is required to maintain isthmic identity
Developmental biology, 2007Co-Authors: Claire A. Canning, Carol Irving, Ivor Mason, Lily Lee, C. Michael JonesAbstract:Fibroblast growth factor 8 (FGF8) is expressed at the mid–hindbrain boundary and is an important signal emanating from the isthmic organizer. Wnt1 is expressed in the caudal midbrain juxtaposed to Fgf8 expression and has been implicated in its regulation. In this study, we examine the requirement for continuous Wnt signaling in the maintenance of Fgf8 expression at the isthmus. We demonstrate that prior to HH10, ongoing Wnt signaling is required to maintain the normal pattern of isthmic Fgf8 expression in ovo. Similarly, in explant assays, sustained Wnt signaling is essential to maintain Fgf8 expression in Rhombomere 1. The mechanism by which Wnt signaling regulates isthmic Fgf8 expression is likely to be a maintenance response rather than an inductive effect. Finally, we show that Wnt maintenance of Fgf8 expression is dependent upon positive feedback by FGF signaling itself, and that Rhombomere 1 does not receive instructive cues from the posterior hindbrain. In summary, these findings establish that a sustained reciprocal interaction between Wnt and FGF signaling is essential to maintain isthmic identity.
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Establishing the trochlear motor axon trajectory: role of the isthmic organiser and Fgf8
Development (Cambridge England), 2002Co-Authors: Carol Irving, Amar Malhas, Sarah Guthrie, Ivor MasonAbstract:Formation of the trochlear nerve within the anterior hindbrain provides a model system to study a simple axonal projection within the vertebrate central nervous system. We show that trochlear motor neurons are born within the isthmic organiser and also immediately posterior to it in anterior Rhombomere 1. Axons of the most anterior cells follow a dorsal projection, which circumnavigates the isthmus, while those of more posterior trochlear neurons project anterodorsally to enter the isthmus. Once within the isthmus, axons form large fascicles that extend to a dorsal exit point. We investigated the possibility that the projection of trochlear axons towards the isthmus and their subsequent growth within that tissue might depend upon chemoattraction. We demonstrate that both isthmic tissue and Fgf8 protein are attractants for trochlear axons in vitro, while ectopic Fgf8 causes turning of these axons away from their normal routes in vivo. Both inhibition of FGF receptor activation and inhibition of Fgf8 function in vitro affect formation of the trochlear projection within explants in a manner consistent with a guidance function of Fgf8 during trochlear axon navigation.
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Regulation and function of FGF8 in patterning of midbrain and anterior hindbrain.
Biochemistry and cell biology = Biochimie et biologie cellulaire, 2000Co-Authors: Ivor Mason, David J. Chambers, Huma Shamim, Jennifer Walshe, Carol IrvingAbstract:In this article, an adjunct to a platform presentation at the Winternational 2000 Symposium, we summarize the recent findings of this group concerning the regulation and functions of FGF8 expressed at the isthmus of the developing brain. We show that several different FGF8 isoforms, ectopically expressed in midbrain or posterior forebrain, are able to mimic the proliferative and patterning functions previously attributed to the isthmus in tissue grafting studies. Moreover, we also show that FGF8 protein is sufficient to induce an ectopic isthmic organiser (Fgf-8+, Gbx2+) in anterior midbrain. We also provide evidence that isthmic FGF8 patterns anterior hindbrain, repressing Hox-a2 expression and setting aside a territory of the brain that includes the cerebellar anlage. We show that these effects of FGF8 are likely to be mediated via FGFR1 and be modulated by the putative FGF antagonist, Sprouty2, identified using a differential display screen. Finally, we provide evidence that the onset of Fgf8 expression is regulated by En1 and that its expression at the isthmus is subsequently maintained by a specific and direct interaction between Rhombomere 1 and midbrain.
Alexandra L. Joyner - One of the best experts on this subject based on the ideXlab platform.
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gli3 coordinates three dimensional patterning and growth of the tectum and cerebellum by integrating shh and fgf8 signaling
Development, 2008Co-Authors: Sandra Blaess, Daniel Stephen, Alexandra L. JoynerAbstract:The coordination of anterior-posterior (AP) and dorsal-ventral (DV) patterning of the mesencephalon (mes) and Rhombomere 1 (r1) is instrumental for the development of three distinct brain structures: the tectum and cerebellum dorsally and the tegmentum ventrally. Patterning of the mes/r1 is primarily mediated by signaling molecules secreted from two organizers: sonic hedgehog (Shh) from the floor plate (DV) and Fgf8 from the isthmus (AP). Gli3, a zinc-finger transcription factor in the Shh signaling pathway, has been implicated in regulating Fgf8 expression and is therefore a potential candidate for coordinating the action of the two organizers. By inactivating mouse Gli3 at successive embryonic time points in vivo, we uncovered the extent and the underlying mechanism of Gli3 function in the mes/r1. We demonstrate that before E9.0, Gli3 is required for establishing a distinct posterior tectum, isthmus and cerebellum, but does not play a role in the development of the tegmentum. Between E9.0 and E11.0, Gli3 continues to be required for isthmus and cerebellum development, but primarily for defining the cerebellar foliation pattern. We show that Gli3 regulates patterning of the isthmus and cerebellar anlage by confining Fgf8 expression to the isthmus, and attenuates growth of dorsal r1 (before E11.0) and the dorsal mes and isthmus (beyond E11.0) through regulation of cell proliferation and viability. In conclusion, our results show that Gli3 is essential for the coordinated three-dimensional patterning and growth of the dorsal mes/r1.
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Specific regions within the embryonic midbrain and cerebellum require different levels of FGF signaling during development
Development (Cambridge England), 2008Co-Authors: M. Albert Basson, Salvador Martinez, Alexandra L. Joyner, Ivor Mason, Diego Echevarria, Christina P. Ahn, Anamaria Sudarov, Gail R MartinAbstract:Prospective midbrain and cerebellum formation are coordinated by FGF ligands produced by the isthmic organizer. Previous studies have suggested that midbrain and cerebellum development require different levels of FGF signaling. However, little is known about the extent to which specific regions within these two parts of the brain differ in their requirement for FGF signaling during embryogenesis. Here, we have explored the effects of inhibiting FGF signaling within the embryonic mouse midbrain (mesencephalon) and cerebellum (Rhombomere 1) by misexpressing sprouty2 (Spry2) from an early stage. We show that such Spry2 misexpression moderately reduces FGF signaling, and that this reduction causes cell death in the anterior mesencephalon, the region furthest from the source of FGF ligands. Interestingly, the remaining mesencephalon cells develop into anterior midbrain, indicating that a low level of FGF signaling is sufficient to promote only anterior midbrain development. Spry2 misexpression also affects development of the vermis, the part of the cerebellum that spans the midline. We found that, whereas misexpression of Spry2 alone caused loss of the anterior vermis, reducing FGF signaling further, by decreasing Fgf8 gene dose, resulted in loss of the entire vermis. Our data suggest that cell death is not responsible for vermis loss, but rather that it fails to develop because reducing FGF signaling perturbs the balance between vermis and roof plate development in Rhombomere 1. We suggest a molecular explanation for this phenomenon by providing evidence that FGF signaling functions to inhibit the BMP signaling that promotes roof plate development.
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Morphogenetic and Cellular Movements that Shape the Mouse Cerebellum: Insights from Genetic Fate Mapping
Neuron, 2005Co-Authors: Sema K. Sgaier, Sandrine Millet, Melissa P. Villanueva, Frada Berenshteyn, Christian Song, Alexandra L. JoynerAbstract:We used the cerebellum as a model to study the morphogenetic and cellular processes underlying the formation of elaborate brain structures from a simple neural tube, using an inducible genetic fate mapping approach in mouse. We demonstrate how a 90° rotation between embryonic days 9 and 12 converts the rostral-caudal axis of dorsal Rhombomere 1 into the medial-lateral axis of the wing-like bilateral cerebellar primordium. With the appropriate use of promoters, we marked specific medial-lateral domains of the cerebellar primordium and derived a positional fate map of the murine cerebellum. We show that the adult medial cerebellum is produced by expansion, rather than fusion, of the thin medial primordium. Furthermore, ventricular-derived cells maintain their original medial-lateral coordinates into the adult, whereas rhombic lip-derived granule cells undergo lateral to medial posterior transverse migrations during foliation. Thus, we show that progressive changes in the axes of the cerebellum underlie its genesis.
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Cell behaviors and genetic lineages of the mesencephalon and Rhombomere 1.
Neuron, 2004Co-Authors: Mark Zervas, Sandrine Millet, Sohyun Ahn, Alexandra L. JoynerAbstract:Brain structures derived from the mesencephalon (mes) and Rhombomere 1 (r1) modulate distinct motor and sensory modalities. The precise origin and cellular behaviors underpinning the cytoarchitectural organization of the mes and r1, however, are unknown. Using a novel inducible genetic fate mapping approach in mouse, we determined the fate and lineage relationships of mes/r1 cells with fine temporal and spatial resolution. We demonstrate that the mes and r1 are neuromeres that along with the isthmic organizer are partitioned along the anterior-posterior axis by lineage restriction boundaries established sequentially between E8.5 and E9.5. Furthermore, a small group of cells originating from the most posterior mes exhibit anterior intracompartmental expansion and contribute throughout the inferior colliculus. Finally, we also uncovered transient and differential genetic lineages of ventral midbrain dopaminergic and ventral hindbrain serotonergic neuronal precursors with respect to Wnt1 and Gli1 expression.
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How does Fgf signaling from the isthmic organizer induce midbrain and cerebellum development
Development growth & differentiation, 2004Co-Authors: Tatsuya Sato, Alexandra L. Joyner, Harukazu NakamuraAbstract:The mesencephalic/Rhombomere 1 border (isthmus) is an organizing center for early development of midbrain and cerebellum. In this review, we summarize recent progress in studies of Fgf signaling in the isthmus and discuss how the isthmus instructs the differentiation of the midbrain versus cerebellum. Fgf8 is shown to play a pivotal role in isthmic organizer activity. Only a strong Fgf signal mediated by Fgf8b activates the Ras-extracellular signal-regulated kinase (ERK) pathway, and this is sufficient to induce cerebellar development. A lower level of signaling transduced by Fgf8a, Fgf17 and Fgf18 induce midbrain development. Numerous feedback loops then maintain appropriate mesencephalon/Rhombomere1 and organizer gene expression.
Carol Irving - One of the best experts on this subject based on the ideXlab platform.
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Sustained interactive Wnt and FGF signaling is required to maintain isthmic identity
Developmental biology, 2007Co-Authors: Claire A. Canning, Carol Irving, Ivor Mason, Lily Lee, C. Michael JonesAbstract:Fibroblast growth factor 8 (FGF8) is expressed at the mid–hindbrain boundary and is an important signal emanating from the isthmic organizer. Wnt1 is expressed in the caudal midbrain juxtaposed to Fgf8 expression and has been implicated in its regulation. In this study, we examine the requirement for continuous Wnt signaling in the maintenance of Fgf8 expression at the isthmus. We demonstrate that prior to HH10, ongoing Wnt signaling is required to maintain the normal pattern of isthmic Fgf8 expression in ovo. Similarly, in explant assays, sustained Wnt signaling is essential to maintain Fgf8 expression in Rhombomere 1. The mechanism by which Wnt signaling regulates isthmic Fgf8 expression is likely to be a maintenance response rather than an inductive effect. Finally, we show that Wnt maintenance of Fgf8 expression is dependent upon positive feedback by FGF signaling itself, and that Rhombomere 1 does not receive instructive cues from the posterior hindbrain. In summary, these findings establish that a sustained reciprocal interaction between Wnt and FGF signaling is essential to maintain isthmic identity.
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Establishing the trochlear motor axon trajectory: role of the isthmic organiser and Fgf8
Development (Cambridge England), 2002Co-Authors: Carol Irving, Amar Malhas, Sarah Guthrie, Ivor MasonAbstract:Formation of the trochlear nerve within the anterior hindbrain provides a model system to study a simple axonal projection within the vertebrate central nervous system. We show that trochlear motor neurons are born within the isthmic organiser and also immediately posterior to it in anterior Rhombomere 1. Axons of the most anterior cells follow a dorsal projection, which circumnavigates the isthmus, while those of more posterior trochlear neurons project anterodorsally to enter the isthmus. Once within the isthmus, axons form large fascicles that extend to a dorsal exit point. We investigated the possibility that the projection of trochlear axons towards the isthmus and their subsequent growth within that tissue might depend upon chemoattraction. We demonstrate that both isthmic tissue and Fgf8 protein are attractants for trochlear axons in vitro, while ectopic Fgf8 causes turning of these axons away from their normal routes in vivo. Both inhibition of FGF receptor activation and inhibition of Fgf8 function in vitro affect formation of the trochlear projection within explants in a manner consistent with a guidance function of Fgf8 during trochlear axon navigation.
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Regulation and function of FGF8 in patterning of midbrain and anterior hindbrain.
Biochemistry and cell biology = Biochimie et biologie cellulaire, 2000Co-Authors: Ivor Mason, David J. Chambers, Huma Shamim, Jennifer Walshe, Carol IrvingAbstract:In this article, an adjunct to a platform presentation at the Winternational 2000 Symposium, we summarize the recent findings of this group concerning the regulation and functions of FGF8 expressed at the isthmus of the developing brain. We show that several different FGF8 isoforms, ectopically expressed in midbrain or posterior forebrain, are able to mimic the proliferative and patterning functions previously attributed to the isthmus in tissue grafting studies. Moreover, we also show that FGF8 protein is sufficient to induce an ectopic isthmic organiser (Fgf-8+, Gbx2+) in anterior midbrain. We also provide evidence that isthmic FGF8 patterns anterior hindbrain, repressing Hox-a2 expression and setting aside a territory of the brain that includes the cerebellar anlage. We show that these effects of FGF8 are likely to be mediated via FGFR1 and be modulated by the putative FGF antagonist, Sprouty2, identified using a differential display screen. Finally, we provide evidence that the onset of Fgf8 expression is regulated by En1 and that its expression at the isthmus is subsequently maintained by a specific and direct interaction between Rhombomere 1 and midbrain.
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Signalling by FGF8 from the isthmus patterns anterior hindbrain and establishes the anterior limit of Hox gene expression.
Development (Cambridge England), 2000Co-Authors: Carol Irving, Ivor MasonAbstract:Current evidence suggests that the anterior segment of the vertebrate hindbrain, Rhombomere 1, gives rise to the entire cerebellum. It is situated where two distinct developmental patterning mechanisms converge: graded signalling from an organising centre (the isthmus) located at the midbrain/hindbrain boundary confronts segmentation of the hindbrain. The unique developmental fate of Rhombomere 1 is reflected by it being the only hindbrain segment in which no Hox genes are expressed. In this study we show that ectopic FGF8 protein, a candidate for the isthmic organising activity, is able to induce and repress gene expression within the hindbrain in a manner appropriate to Rhombomere 1. Using a heterotopic, heterospecific grafting strategy we demonstrate that Rhombomere 1 is able to express Hox genes but that both isthmic tissue and FGF8 inhibit their expression. Inhibition of FGF8 function in vivo shows that it is responsible for defining the anterior limit of Hox gene expression within the developing brain and thereby specifies the extent of the rl territory. Previous studies have suggested that a retinoid morphogen gradient determines the axial limit of expression of individual Hox genes within the hindbrain. We propose a model whereby activation by retinoids is antagonised by inhibition by FGF8 in the anterior hindbrain to set aside the territory from which the cerebellum will develop.
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Regeneration of isthmic tissue is the result of a specific and direct interaction between Rhombomere 1 and midbrain.
Development (Cambridge England), 1999Co-Authors: Carol Irving, Ivor MasonAbstract:The midbrain-hindbrain boundary, or isthmus, is the source of signals that are responsible for regional specification of both the midbrain and anterior hindbrain. Fibroblast growth factor 8 (Fgf8) is expressed specifically at the isthmus and there is now good evidence that it forms at least part of the patterning signal. In this study, we use Fgf8 as a marker for isthmic cells to examine how interactions between midbrain and hindbrain can regenerate isthmic tissue and, thereby, gain insight into the normal formation and/or maintenance of the isthmus. We show that Fgf8-expressing tissue with properties of the isthmic organiser is generated when midbrain and Rhombomere 1 tissue are juxtaposed but not when midbrain contacts any other Rhombomere. The use of chick/quail chimeras shows that the isthmic tissue is largely derived from Rhombomere 1. In a few cases a small proportion of the Fgf8-positive cells were of midbrain origin but this appears to be the result of a local respecification to a hindbrain phenotype, a process mimicked by ectopic FGF8. Studies in vitro show that the induction of Fgf8 is the result of a direct planar interaction between the two tissues and involves a diffusible signal.