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Magdalena Götz - One of the best experts on this subject based on the ideXlab platform.

  • the role of PAX6 in regulating the orientation and mode of cell division of progenitors in the mouse cerebral cortex
    Journal of Cell Science, 2011
    Co-Authors: Maki Asami, Jovica Ninkovic, Timm Schroeder, Wieland B Huttner, Gregor A Pilz, Leanne Godinho, Magdalena Götz
    Abstract:

    Successful brain development requires tight regulation of sequential symmetric and asymmetric cell division. Although PAX6 is known to exert multiple roles in the developing nervous system, its role in the regulation of cell division is unknown. Here, we demonstrate profound alterations in the orientation and mode of cell division in the cerebral cortex of mice deficient in PAX6 function (PAX6Sey/Sey) or after acute induced deletion of PAX6. Live imaging revealed an increase in non-vertical cellular cleavage planes, resulting in an increased number of progenitors with unequal inheritance of the apical membrane domain and adherens junctions in the absence of PAX6 function. This phenotype appears to be mediated by the direct PAX6 target Spag5, a microtubule-associated protein, reduced levels of which result in the replication of the PAX6 phenotype of altered cell division orientation. In addition, lack of PAX6 also results in premature delamination of progenitor cells from the apical surface due to an overall decrease in proteins mediating anchoring at the ventricular surface. Moreover, continuous long-term imaging in vitro revealed that PAX6-deficient progenitors generate daughter cells with asymmetric fates at higher frequencies. These data demonstrate a cell-autonomous role for PAX6 in regulating the mode of cell division independently of apicobasal polarity and cell-cell interactions. Taken together, our work reveals several direct effects that the Transcription Factor PAX6 has on the machinery that mediates the orientation and mode of cell division.

  • the Transcription Factor PAX6 regulates survival of dopaminergic olFactory bulb neurons via crystallin αa
    Neuron, 2010
    Co-Authors: Jovica Ninkovic, Luisa Pinto, Stefania Petricca, Alexandra Lepier, Jian Sun, Michael A Rieger, Timm Schroeder, Ales Cvekl, Jack Favor, Magdalena Götz
    Abstract:

    Most neurons in the adult mammalian brain survive for the entire life of an individual. However, it is not known which Transcriptional pathways regulate this survival in a healthy brain. Here, we identify a pathway regulating neuronal survival in a highly subtype-specific manner. We show that the Transcription Factor PAX6 expressed in dopaminergic neurons of the olFactory bulb regulates the survival of these neurons by directly controlling the expression of crystallin αA (CryαA), which blocks apoptosis by inhibition of procaspase-3 activation. Re-expression of CryαA fully rescues survival of PAX6-deficient dopaminergic interneurons in vivo and knockdown of CryαA by shRNA in wild-type mice reduces the number of dopaminergic OB interneurons. Strikingly, PAX6 utilizes different DNA-binding domains for its well-known role in fate specification and this role of regulating the survival of specific neuronal subtypes in the mature, healthy brain.

  • loss and gain of function analyses reveal targets of PAX6 in the developing mouse telencephalon
    Molecular and Cellular Neuroscience, 2007
    Co-Authors: Pontus C Holm, Michael T Mader, Nicole Haubst, Andrea Wizenmann, Mikael Sigvardsson, Magdalena Götz
    Abstract:

    Appropriate neurogenesis and patterning of the forebrain requires the Transcription Factor PAX6, yet it is largely unknown how PAX6 exerts its effects at the molecular level. To characterize PAX6-mediated regulation of gene expression during murine forebrain neurogenesis, we performed microarray analysis with tissue from the dorsal PAX6-dependent telencephalon and the ventral PAX6-negative telencephalon at the onset of neurogenesis (E12) and at mid-neurogenesis (E15) in wild-type and PAX6-deficient mutant littermates. In the PAX6-deficient cortex the expression levels of various Transcription Factors involved in neurogenesis (like Satb2, Nfia, AP-2gamma, NeuroD6, Ngn2, Tbr2, Bhlhb5) and the retinoic acid signalling molecule Rlbp1 were reduced. Regulation by PAX6 could be confirmed upon electroporation of a PAX6- and a dominant-negative PAX6-containing vector into embryonic cortex. Taken together, our data reveal novel insights into the molecular pathways regulated by PAX6 during cortical neurogenesis. Most intriguingly, this analysis revealed time- and region-specific differences in PAX6-mediated Transcription, explaining the specific function of PAX6 at early and later stages of neurogenesis.

  • Neuronal fate determinants of adult olFactory bulb neurogenesis.
    Nature Neuroscience, 2005
    Co-Authors: Michael A Hack, Ruth Ashery-padan, Armen Saghatelyan, Antoine De Chevigny, Alexander Pfeifer, Pierre-marie Lledo, Magdalena Götz
    Abstract:

    Adult neurogenesis in mammals is restricted to two small regions, including the olFactory bulb, where GABAergic and dopaminergic interneurons are newly generated throughout the entire lifespan. However, the mechanisms directing them towards a specific neuronal phenotype are not yet understood. Here, we demonstrate the dual role of the Transcription Factor PAX6 in generating neuronal progenitors and also in directing them towards a dopaminergic periglomerular phenotype in adult mice. We present further evidence that dopaminergic periglomerular neurons originate in a distinct niche, the rostral migratory stream, and are fewer derived from precursors in the zone lining the ventricle. This regionalization of the adult precursor cells is further supported by the restricted expression of the Transcription Factor Olig2, which specifies transit-amplifying precursor fate and opposes the neurogenic role of PAX6. Together, these data explain both extrinsic and intrinsic mechanisms controlling neuronal identity in adult neurogenesis.

  • molecular dissection of PAX6 function the specific roles of the paired domain and homeodomain in brain development
    Development, 2004
    Co-Authors: Nicole Haubst, Anastassia Stoykova, Jack Favor, Joachim Berger, Venugopal Radjendirane, Jochen Graw, Grady F Saunders, Magdalena Götz
    Abstract:

    The Transcription Factor PAX6 plays a key role during development of various organs, including the brain where it affects cell fate, cell proliferation and patterning. To understand how PAX6 coordinates these diverse effects at the molecular level, we examined the role of distinct DNA-binding domains of PAX6, the homeodomain (HD), the paired domain (PD) and its splice variant (5a), using loss- and gain-of-function approaches. Here we show that the PD is necessary for the regulation of neurogenesis, cell proliferation and patterning effects of PAX6, since these aspects are severely affected in the developing forebrain of the PAX6Aey18 mice with a deletion in the PD but intact homeo- and transactivation domains. In contrast, a mutation of the HD lacking DNA-binding (PAX64Neu) resulted in only subtle defects of forebrain development. We further demonstrate distinct roles of the two splice variants of the PD. Retrovirally mediated overexpression of PAX6 containing exon 5a inhibited cell proliferation without affecting cell fate, while PAX6 containing the canonical form of the PD lacking exon 5a affected simultaneously cell fate and proliferation. These results therefore demonstrate a key role of the PD in brain development and implicate splicing as a pivotal Factor regulating the potent neurogenic role of PAX6.

David Price - One of the best experts on this subject based on the ideXlab platform.

  • tissue specific actions of PAX6 on proliferation and differentiation balance in developing forebrain are foxg1 dependent
    iScience, 2018
    Co-Authors: Idoia Quintanaurzainqui, John O. Mason, Martine Manuel, Zrinko Kozic, Soham Mitra, Tian Tian, David Price
    Abstract:

    Summary Differences in the growth and maturation of diverse forebrain tissues depend on region-specific Transcriptional regulation. Individual Transcription Factors act simultaneously in multiple regions that develop very differently, raising questions about the extent to which their actions vary regionally. We found that the Transcription Factor PAX6 affects the transcriptomes and the balance between proliferation and differentiation in opposite directions in the diencephalon versus cerebral cortex. We tested several possible mechanisms to explain PAX6's tissue-specific actions and found that the presence of the Transcription Factor Foxg1 in the cortex but not in the diencephalon was most influential. We found that Foxg1 is responsible for many of the differences in cell cycle gene expression between the diencephalon and cortex and, in cortex lacking Foxg1, PAX6's action on the balance of proliferation versus differentiation becomes diencephalon like. Our findings reveal a mechanism for generating regional forebrain diversity in which one Transcription Factor completely reverses the actions of another.

  • tissue specific actions of PAX6 on the balance of proliferation and differentiation in developing forebrain are foxg1 dependent
    Social Science Research Network, 2018
    Co-Authors: Idoia Quintanaurzainqui, John O. Mason, Martine Manuel, Zrinko Kozic, Soham Mitra, Tian Tian, David Price
    Abstract:

    Differences in the growth and maturation of diverse forebrain tissues depend on region-specific Transcriptional regulation. Individual Transcription Factors act simultaneously in multiple regions that develop very differently, raising questions about the extent to which their actions vary regionally. We found that the Transcription Factor PAX6 affects the transcriptomes and the balance between proliferation and differentiation in opposite directions in diencephalon versus cerebral cortex. We tested several possible mechanisms to explain PAX6’s tissue-specific actions and found that the presence of the Transcription Factor Foxg1 in cortex but not diencephalon was most influential. We found that Foxg1 is responsible for many of the differences in cell cycle gene expression between diencephalon and cortex and, in cortex lacking Foxg1, PAX6’s action on the balance of proliferation versus differentiation becomes diencephalon-like. Our findings reveal a mechanism for generating regional forebrain diversity in which one Transcription Factor completely reverses the actions of another.

  • tissue specific actions of PAX6 on proliferation differentiation balance in the developing forebrain are foxg1 dependent
    bioRxiv, 2018
    Co-Authors: Idoia Quintanaurzainqui, John O. Mason, Martine Manuel, Zrinko Kozic, Soham Mitra, Tian Tian, David Price
    Abstract:

    Differences in the growth and maturation of diverse forebrain tissues depends on region-specific Transcriptional regulation. Individual Transcription Factors act simultaneously in multiple regions that develop very differently, raising questions about the extent to which their actions vary regionally. We found that the Transcription Factor PAX6 affects the transcriptomes and the balance between proliferation and differentiation in opposite directions in murine diencephalon versus cortex. We tested several possible mechanisms to explain PAX6 tissue-specific actions and found that the presence of the Transcription Factor Foxg1 in cortex but not diencephalon was most influential. We found that Foxg1 is responsible for many of the differences in cell cycle gene expression between diencephalon and cortex. In cortex lacking Foxg1, PAX6 action on the balance of proliferation versus differentiation became diencephalon-like. Our findings reveal a mechanism for generating regional forebrain diversity in which the actions of one Transcription Factor completely reverse the actions of another.

  • the generation of superficial cortical layers is regulated by levels of the Transcription Factor PAX6
    Cerebral Cortex, 2011
    Co-Authors: Petrina A Georgala, Martine Manuel, David Price
    Abstract:

    The ventricular zone (VZ) of the embryonic dorsal telencephalon is a major site for generating cortical projection neurons. The Transcription Factor PAX6 is highly expressed in apical progenitors (APs) residing in the VZ from the earliest stages of corticogenesis. Previous studies mainly focused on PAX6(-/-) mice have implicated PAX6 in regulating cortical progenitor proliferation, neurogenesis, and formation of superficial cortical layers. We analyzed the developing cortex of PAX77 transgenic mice that overexpress PAX6 in its normal domains of expression. We show that PAX6 overexpression increases cell cycle length of APs and drives the system toward neurogenesis. These effects are specific to late stages of corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express PAX6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, whereas radial migration and lamina specification of cortical neurons are not affected by PAX6 overexpression. Conditional deletion of PAX6 in cortical progenitors at midstages of corticogenesis, by using a tamoxifen-inducible Emx1-CreER line, affected both numbers and specification of late-born neurons in superficial layers of the mutant cortex. Our analyses suggest that correct levels of PAX6 are essential for normal production of superficial layers of the cortex.

  • positive autoregulation of the Transcription Factor PAX6 in response to increased levels of either of its major isoforms PAX6 or PAX6 5a in cultured cells
    BMC Developmental Biology, 2006
    Co-Authors: Jeni Pinson, John O. Mason, Ian T Simpson, David Price
    Abstract:

    Background: PAX6 is a Transcription Factor essential for normal development of the eyes and nervous system. It has two major isoforms, PAX6 and PAX6(5a), and the ratios between their expression levels vary within narrow limits. We tested the effects of overexpressing either one or other isoform on endogenous PAX6 expression levels in Neuro2A and NIH3T3 cells. Results: We found that both isoforms caused an up-regulation of endogenous PAX6 expression in cells with (Neuro2A) or without (NIH3T3) constitutive PAX6 expression. Western blots showed that cells stably transfected with constructs expressing either PAX6 or PAX6(5a) contained raised levels of both PAX6 and PAX6(5a). Quantitative RT-PCR confirmed an increase in levels of PAX6(5a) mRNA in cells containing PAX6-expressing constructs and an increase in levels of PAX6 mRNA in cells containing PAX6(5a)-expressing constructs. The fact that the introduction of constructs expressing only one isoform increased the cellular levels of not only that isoform but also the other indicates that activation of the endogenous PAX6 locus occurred. The ratio between the levels of the two isoforms was maintained close to physiological values. The overexpression of either isoform in neuroblastoma (Neuro2A) cell lines also promoted morphological change and an increase in β-III-tubulin expression, indicating an increase in neurogenesis. Conclusion: Our results demonstrate that PAX6 can up-regulate production of PAX6 protein from an entire intact endogenous PAX6 locus in its genomic environment. This adds to previous studies showing that PAX6 can up-regulate reporter expression driven by isolated PAX6 regulatory elements. Furthermore, our results suggest that an important function of positive feedback might be to stabilise the relative levels of PAX6 and PAX6(5a).

Guillermo Estivilltorrus - One of the best experts on this subject based on the ideXlab platform.

  • the Transcription Factor PAX6 is required for development of the diencephalic dorsal midline secretory radial glia that form the subcommissural organ
    Mechanisms of Development, 2001
    Co-Authors: Tania Vitalis, Guillermo Estivilltorrus, P Fernandezllebrez, David J. Price
    Abstract:

    During brain development, PAX6 is expressed in specific regions of the diencephalon including secretory cells of the subcommissural organ (SCO), a circumventricular organ at the forebrain–midbrain boundary that originates from the pretectal dorsal midline neuroepithelial cells beneath the posterior commissure (PC). Homozygous small eye (Sey/Sey) mice lack functional PAX6 protein and fail to develop the SCO, a normal PC and the pineal gland. Small eye heterozygotes (Sey/1) show defective development of the SCO’s basal processes which normally penetrate the PC, indicating that normal development of the gland requires normal PAX6 gene-dosage. A correlation between the defects of SCO formation and altered R- and OB-cadherin expression patterns in the SCO is observed in mutants suggesting a role for cadherins in SCO development. q 2001 Elsevier Science Ltd. All rights reserved.

  • the Transcription Factor PAX6 is required for development of the diencephalic dorsal midline secretory radial glia that form the subcommissural organ
    Mechanisms of Development, 2001
    Co-Authors: Guillermo Estivilltorrus, Tania Vitalis, P Fernandezllebrez, David Price
    Abstract:

    During brain development, PAX6 is expressed in specific regions of the diencephalon including secretory cells of the subcommissural organ (SCO), a circumventricular organ at the forebrain-midbrain boundary that originates from the pretectal dorsal midline neuroepithelial cells beneath the posterior commissure (PC). Homozygous small eye (Sey/Sey) mice lack functional PAX6 protein and fail to develop the SCO, a normal PC and the pineal gland. Small eye heterozygotes (Sey/+) show defective development of the SCO's basal processes which normally penetrate the PC, indicating that normal development of the gland requires normal PAX6 gene-dosage. A correlation between the defects of SCO formation and altered R- and OB-cadherin expression patterns in the SCO is observed in mutants suggesting a role for cadherins in SCO development.

Peter Gruss - One of the best experts on this subject based on the ideXlab platform.

  • PAX6 is required for the normal development of the forebrain axonal connections
    Development, 2002
    Co-Authors: Lucy Jones, Anastassia Stoykova, Peter Gruss, Guillermina Lopezbendito, Zoltan Molnar
    Abstract:

    The Transcription Factor PAX6 has been implicated in forebrain patterning, cerebral cortical arealization and in development of thalamocortical connections. Using a PAX6/lacZ knockout mouse, in which the endogenous PAX6 expression is reflected by β-galactosidase activity, we have studied the consequences of the loss of PAX6 function on thalamocortical (TCA) and corticofugal axon (CFA) pathfinding during the period of embryonic day (E) 14.5 to E18.5. Carbocyanine dye tracing in PAX6 heterozygotes ( PAX6 +/- ) and PAX6 wild-type ( PAX6 +/+ ) brains revealed that CFAs and TCAs temporarily arrested their growth at E14.5 at the border of the β -galactosidase-positive region at the pallial/subpallial boundary (PSPB), before they continued towards their targets. However, in PAX6 homozygous ( PAX6 -/- ) embryos, CFAs and TCAs were unable to encounter each other at the PSPB and reach their final targets. Instead of crossing the PSPB, they had the tendency to descend into the ventral pallium in large aberrant fascicles. In addition, cells with a presumptive guide-post function, which are normally situated in the ventral thalamus, internal capsule and hypothalamus, were more dispersed in the hypothalamus and ventral pallium. These pathfinding defects were confirmed by immunohistochemistry for L1 and TAG1, markers of the early axonal connections. The aberrant development of axonal connections in absence of PAX6 function appear to be related to ultrastructural defects of cells along the PSPB, as well as to a failure of axonal guidance molecule expression, including Sema3c and Sema5a.

  • PAX6 is required for establishing naso-temporal and dorsal characteristics of the optic vesicle
    Development (Cambridge England), 2002
    Co-Authors: Nicole Bäumer, Ruth Ashery-padan, Till Marquardt, Anastassia Stoykova, Kamal Chowdhury, Peter Gruss
    Abstract:

    The establishment of polarity is an important step during organ development. We assign a function for the paired and homeodomain Transcription Factor PAX6 in axis formation in the retina. PAX6 is a key Factor of the highly conserved genetic network implicated in directing the initial phases of eye development. We recently demonstrated that PAX6 is also essential for later aspects of eye development, such as lens formation and retinogenesis. In this study, we present evidence that a highly conserved intronic enhancer, α, in the PAX6 gene is essential for the establishment of a distalhigh-proximallow gradient of PAX6 activity in the retina. In the mature retina, the activity mediated by the α-enhancer defines a population of retinal ganglion cells that project to two sickle-shaped domains in the superior colliculus and lateral geniculate nucleus. Deletion of the α-enhancer in vivo revealed that retinal PAX6 expression is regulated in two complementary topographic domains. We found that PAX6 activity is required for the establishment, as well as the maintenance of dorsal and nasotemporal characteristics in the optic vesicle and, later, the optic cup.

  • isolation and characterization of a downstream target of PAX6 in the mammalian retinal primordium
    Development, 2001
    Co-Authors: Gilbert Bernier, Wolfgang Vukovich, Lorenz Neidhardt, Bernhard G Herrmann, Peter Gruss
    Abstract:

    The Transcription Factor PAX6 is required for eye morphogenesis in humans, mice and insects, and can induce ectopic eye formation in vertebrate and invertebrate organisms. Although the role of PAX6 has intensively been studied, only a limited number of genes have been identified that depend on PAX6 activity for their expression in the mammalian visual system. Using a large-scale in situ hybridization screen approach, we have identified a novel gene expressed in the mouse optic vesicle. This gene, Necab , encodes a putative cytoplasmic Ca 2+ -binding protein and coincides with PAX6 expression pattern in the neural ectoderm of the optic vesicle and in the forebrain pretectum. Remarkably, Necab expression is absent in both structures in PAX6 mutant embryos. By contrast, the optic vesicle-expressed homeobox genes Rx , Six3 , Otx2 and Lhx2 do not exhibit an altered expression pattern. Using gain-of-function experiments, we show that PAX6 can induce ectopic expression of Necab , suggesting that Necab is a direct or indirect Transcriptional target of PAX6 . In addition, we have found that Necab misexpression can induce ectopic expression of the homeobox gene Chx10 , a Transcription Factor implicated in retina development. Taken together, our results provide evidence that Necab is genetically downstream of PAX6 and that it is a part of a signal transduction pathway in retina development.

  • PAX6 controls radial glia differentiation in the cerebral cortex
    Neuron, 1998
    Co-Authors: Magdalena Götz, Anastassia Stoykova, Peter Gruss
    Abstract:

    Radial glia cells perform a dual function in the developing nervous system as precursor cells and guides for migrating neurons. We show here that during forebrain neurogenesis, the Transcription Factor PAX6 is specifically localized in radial glia cells of the cortex but not of the basal telencephalon. In PAX6-deficient mice, cortical radial glia cells were altered in their morphology, number, tenascin-C (TN-C) expression, and cell cycle. We show that some of these alterations are cell-autonomous, whereas others were rescued by coculturing with wild-type cortical cells. Our results suggest that PAX6 plays an essential role in the differentiation of cortical radial glia. Thus, despite their widespread distribution, radial glia cells are regionally specified in the developing CNS.

  • PAX6 dependent regulation of adhesive patterning r cadherin expression and boundary formation in developing forebrain
    Development, 1997
    Co-Authors: Anastasia Stoykova, Magdalena Götz, Peter Gruss, J Price
    Abstract:

    Mutations in the gene for the Transcription Factor, PAX6, induce marked developmental abnormalities in the CNS and the eye, but the cellular mechanisms that underlie the phenotype are unknown. We have examined the adhesive properties of cells from the developing forebrain in Small eye, the PAX6 mutant mouse. We have found that the segregation normally observed in aggregates of cortical and striatal cells in an in vitro assay is lost in Small eye. This correlates with an alteration of in vivo expression of the homophilic adhesion molecule, R-cadherin. Moreover, the boundary between cortical and striatal regions of the telencephalon is dramatically altered in Small eye: radial glial fascicles do not form at the border, and the normal expression of R-cadherin and tenascin-C at the border is lost. These data suggest a link between the Transcription Factor, PAX6, R-cadherin expression, cellular adhesion and boundary formation between developing forebrain regions.

David J. Price - One of the best experts on this subject based on the ideXlab platform.

  • Loss of PAX6 Causes Regional Changes in Dll1 Expression in Developing Cerebral Cortex
    Frontiers Media S.A., 2019
    Co-Authors: Elena Dorà, David J. Price, John O. Mason
    Abstract:

    The Transcription Factor PAX6 controls multiple aspects of forebrain development. Conditional deletion of PAX6 in embryonic mouse cortex causes increased proliferation of cortical progenitor cells and a concomitant decrease in neural differentiation. Notch signaling regulates the balance between proliferation and differentiation of cortical progenitor cells, suggesting a possible connection between PAX6 and Notch signaling. We investigated how expression of the Notch ligand delta-like 1 (Dll1) is altered by loss of PAX6. Acute cortex-specific deletion of PAX6 resulted in a widespread decrease in the density of Dll1+ cells at embryonic days 12.5 and 13.5 (E12.5 and E13.5). In constitutive loss-of-function mutants, decreases in the densities of Dll1+ cells were more limited both spatially and temporally. Controlled over-expression of PAX6 had no detectable effect on Dll1 expression. The proneural Transcription Factor Neurog2 is a target of PAX6 that can activate Dll1 expression and we found clear co-expression of Neurog2 and Dll1 in radial glial progenitors, suggesting that PAX6’s effect on Dll1 could be mediated through Neurog2. However, we found no change in Dll1+ cells in Neurog2−/− cortex suggesting either that Neurog2 is not directly involved, or that its loss of function in embryonic cortex can be compensated for

  • Tissue-Specific Actions of PAX6 on Proliferation and Differentiation Balance in Developing Forebrain Are Foxg1 Dependent
    'Elsevier BV', 2018
    Co-Authors: Idoia Quintana-urzainqui, John O. Mason, Martine Manuel, Soham Mitra, Tian Tian, Zrinko Kozić, David J. Price
    Abstract:

    Summary: Differences in the growth and maturation of diverse forebrain tissues depend on region-specific Transcriptional regulation. Individual Transcription Factors act simultaneously in multiple regions that develop very differently, raising questions about the extent to which their actions vary regionally. We found that the Transcription Factor PAX6 affects the transcriptomes and the balance between proliferation and differentiation in opposite directions in the diencephalon versus cerebral cortex. We tested several possible mechanisms to explain PAX6's tissue-specific actions and found that the presence of the Transcription Factor Foxg1 in the cortex but not in the diencephalon was most influential. We found that Foxg1 is responsible for many of the differences in cell cycle gene expression between the diencephalon and cortex and, in cortex lacking Foxg1, PAX6's action on the balance of proliferation versus differentiation becomes diencephalon like. Our findings reveal a mechanism for generating regional forebrain diversity in which one Transcription Factor completely reverses the actions of another. : Neuroscience; Molecular Neuroscience; Developmental Neuroscience Subject Areas: Neuroscience, Molecular Neuroscience, Developmental Neuroscienc

  • The expression of maker genes of PSPB is similar between control and conditional null mutant.
    2013
    Co-Authors: Yijing Chen, Dario Magnani, Thomas Theil, Thomas Pratt, David J. Price
    Abstract:

    (A) A LacZ reporter allele shows that Emx1Cre causes cortical recombination as far ventrally as the angle region at E13.5. (B,C) Expression of APC around the angle region (blue arrowhead) in (B) control and (C) conditional null mutants at E13.5, confirming loss of APC dorsal to the angle region, in the region labelled for β-galactosidase in A. (D) The E13.5 PSPB (white arrowhead), situated ventral to the angle region of the cortex (blue arrowhead), is marked by the transition from high (dorsal) to lower (ventral) expression of the Transcription Factor PAX6 and by cells of the lateral cortical stream (LCS). (E) In the conditional null mutant, PAX6 expression at the PSPB is similar to the control in D. (F,G) At E13.5, the expression pattern of the Transcription Factor Mash1 is similar between the control in F and the conditional null mutant in G. Expresses is in the subpallium and displays a sharp boundary respecting the medial edge of the PSPB (white arrowhead). (H,I) Similar to the control in H, the E13.5 PSPB in a conditional null mutant in I is marked by the lateral edge of the expression domain of ventrally-expressed Transcription Factor Gsh2 and a prominent RC2-expressing radial glial palisade from this region flanks the PSPB (bracket). Scale bars: A, 200 µm; B&C, 200 µm; D–I, 200 µm.

  • overexpression of PAX6 results in microphthalmia retinal dysplasia and defective retinal ganglion cell axon guidance
    BMC Developmental Biology, 2008
    Co-Authors: Martine Manuel, Thomas Pratt, Glen Jeffery, David J. Price
    Abstract:

    Background The Transcription Factor PAX6 is expressed by many cell types in the developing eye. Eyes do not form in homozygous loss-of-function mouse mutants (PAX6Sey/Sey) and are abnormally small in PAX6Sey/+ mutants. Eyes are also abnormally small in PAX77 mice expressing multiple copies of human PAX6 in addition to endogenous PAX6; protein sequences are identical in the two species. The developmental events that lead to microphthalmia in PAX77 mice are not well-characterised, so it is not clear whether over- and under-expression of PAX6/PAX6 cause microphthalmia through similar mechanisms. Here, we examined the consequences of over-expression for the eye and its axonal connections.

  • the Transcription Factor PAX6 is required for development of the diencephalic dorsal midline secretory radial glia that form the subcommissural organ
    Mechanisms of Development, 2001
    Co-Authors: Tania Vitalis, Guillermo Estivilltorrus, P Fernandezllebrez, David J. Price
    Abstract:

    During brain development, PAX6 is expressed in specific regions of the diencephalon including secretory cells of the subcommissural organ (SCO), a circumventricular organ at the forebrain–midbrain boundary that originates from the pretectal dorsal midline neuroepithelial cells beneath the posterior commissure (PC). Homozygous small eye (Sey/Sey) mice lack functional PAX6 protein and fail to develop the SCO, a normal PC and the pineal gland. Small eye heterozygotes (Sey/1) show defective development of the SCO’s basal processes which normally penetrate the PC, indicating that normal development of the gland requires normal PAX6 gene-dosage. A correlation between the defects of SCO formation and altered R- and OB-cadherin expression patterns in the SCO is observed in mutants suggesting a role for cadherins in SCO development. q 2001 Elsevier Science Ltd. All rights reserved.