Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

Baala, Lekbir; Briault, Sylvain; Etchevers, Heather C.; Laumonnier, Frédéric; Natiq, Abdelhafid; Amiel, Jeanne; Boddaert, Nathalie; Pïcard, Capucine; Sbiti, Aziza; Asermouh, A.; Attié‐Bitach, Tania; Encha‐Razavi, Férechté; Münnich, Arnold; Sefiani, Abdelaziz; Lyonnet, Stanislas

doi:10.1038/ng1993

Cited by 189 publications

(139 citation statements)

References 14 publications

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“…In this context most CC fibers developed and crossed the midline but only a fraction of callosal projections displays pathfinding defects. This is in contrast to the observed CC agenesis in humans (Baala et al 2007) and might indicate species-specific differences.…”

Section: Genes and Development 2481contrasting

confidence: 87%

“…Highest Tbr2 expression is detected between E12 and E16 in IPCs coincident with the peak of murine cortical neurogenesis and decays after E17 (Englund et al 2005;Molyneaux et al 2007). In humans a homozygous chromosomal translocation that disrupts Tbr2 expression is associated with microcephaly, polymicrogyria, corpus callosum (CC) agenesis, cognitive deficits, and severe motor delay with hypotonia (Baala et al 2007). In mice Tbr2 is required for development of the trophectoderm and during germ layer formation, leading to embryonic death before onset of neurogenesis (Russ et al 2000;Arnold et al 2008).…”

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confidence: 99%

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The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone

Arnold¹,

Huang²,

Cheung³

et al. 2008

Genes Dev.

303

289

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The embryonic subventricular zone (SVZ) is a critical site for generating cortical projection neurons; however, molecular mechanisms regulating neurogenesis specifically in the SVZ are largely unknown. The transcription factor Eomes/Tbr2 is transiently expressed in cortical SVZ progenitor cells. Here we demonstrate that conditional inactivation of Tbr2 during early brain development causes microcephaly and severe behavioral deficits. In Tbr2 mutants the number of SVZ progenitor cells is reduced and the differentiation of upper cortical layer neurons is disturbed. Neurogenesis in the adult dentate gyrus but not the subependymal zone is abolished. These studies establish Tbr2 as a key regulator of neurogenesis in the SVZ.Supplemental material is available at http://www.genesdev.org.

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Section: Genes and Development 2481contrasting

confidence: 87%

mentioning

confidence: 99%

The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone

Arnold¹,

Huang²,

Cheung³

et al. 2008

Genes Dev.

303

289

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“…Eomes (also referred to as Tbr2) belongs to the Tbr1/Eomes/Tbet subfamily of genes (Naiche et al, 2005) that were initially found to play essential roles during trophoblast and mesoderm development in mice (Russ et al, 2000;Strumpf et al, 2005). Eomes is also expressed in the developing central nervous system and has been implicated in the development of the human central nervous system; a homozygous breakpoint mutation in a Moroccan family silences Eomes and leads to microcephaly (Baala et al, 2007). Recent studies have also indicated that Eomes is a component of a pathway that regulates glutamatergic neurogenesis in the cerebral cortex and cerebellum in mouse development (Bulfone et al, 1999;Hevner et al, 2006;Quinn et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse

et al. 2008

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SUMMARYThe mechanisms regulating retinal ganglion cell (RGC) development are crucial for retinogenesis and for the establishment of normal vision. However, these mechanisms are only vaguely understood. RGCs are the first neuronal lineage to segregate from pluripotent progenitors in the developing retina. As output neurons, RGCs display developmental features very distinct from those of the other retinal cell types. To better understand RGC development, we have previously constructed a gene regulatory network featuring a hierarchical cascade of transcription factors that ultimately controls the expression of downstream effector genes. This has revealed the existence of a Pou domain transcription factor, Pou4f2, that occupies a key node in the RGC gene regulatory network and that is essential for RGC differentiation. However, little is known about the genes that connect upstream regulatory genes, such as Pou4f2 with downstream effector genes responsible for RGC differentiation. The purpose of this study was to characterize the retinal function of eomesodermin (Eomes), a T-box transcription factor with previously unsuspected roles in retinogenesis. We show that Eomes is expressed in developing RGCs and is a mediator of Pou4f2 function. Pou4f2 directly regulates Eomes expression through a cis-regulatory element within a conserved retinal enhancer. Deleting Eomes in the developing retina causes defects reminiscent of those in Pou4f2 -/-retinas. Moreover, myelin ensheathment in the optic nerves of Eomes -/-embryos is severely impaired, suggesting that Eomes regulates this process. We conclude that Eomes is a crucial regulator positioned immediately downstream of Pou4f2 and is required for RGC differentiation and optic nerve development.

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“…The original T-box family members were identified due to their critical role in embryonic development. In fact, several human genetic diseases are associated with diminished T-box protein function, and the homozygous deletion of T-box proteins such as Brachyury, Eomesodermin (Eomes), and Tbx6 results in a lethal embryonic phenotype in mouse systems (5,7,22,25,26,28,29). The importance of the T-box family in hematopoietic cell development has been more recently recognized with the discovery of T-box expressed in T cells (T-bet) in CD4 ϩ T helper 1 (Th1) cells and the subsequent identification of the overlapping expression profile of Eomes in CD8 ϩ T cells (27,33).…”

mentioning

confidence: 99%

T-bet's Ability To Regulate Individual Target Genes Requires the Conserved T-Box Domain To Recruit Histone Methyltransferase Activity and a Separate Family Member-Specific Transactivation Domain

Lewis¹,

Miller

Miazgowicz³

et al. 2007

Molecular and Cellular Biology

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Appropriate cellular differentiation and specification rely upon the ability of key developmental transcription factors to precisely establish gene expression patterns. These transcription factors often regulate epigenetic events. However, it has been unclear whether this is the only role that they play in functionally regulating developmental gene expression pathways or whether they also participate in downstream transactivation events at the same promoter. The T-box transcription factor family is important in cellular specification events in many developmental systems, and determining the molecular mechanisms by which this family regulates gene expression networks warrants attention. Here, we examine the mechanism by which T-bet, a critical T-box protein in the immune system, influences transcription. T-bet is both necessary and sufficient to induce permissive histone H3-K4 dimethyl modifications at the CXCR3 and IFN-␥ promoters. A T-bet structurefunction analysis revealed that the conserved T-box domain, with a small C-terminal portion, is required for recruiting histone methyltransferase activity to promoters. Interestingly, this function is conserved in the T-box family and is necessary, but not sufficient, to induce transcription, with an independent transactivation activity also required. The requirement for two separable functional activities may ultimately contribute to the stringent role for T-box proteins in establishing specific developmental gene expression pathways.

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Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

Cited by 189 publications

References 14 publications

The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone

The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone

Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse

T-bet's Ability To Regulate Individual Target Genes Requires the Conserved T-Box Domain To Recruit Histone Methyltransferase Activity and a Separate Family Member-Specific Transactivation Domain

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