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

Arnold, Sebastian J.; Huang, Guo-Jen; Cheung, Ankie Tan; Era, Takumi; Nishikawa, Shin Ichi; Bikoff, Elizabeth K.; Molnár, Zoltán; Robertson, Elizabeth J.; Groszer, Matthias

doi:10.1101/gad.475408

Cited by 298 publications

(321 citation statements)

References 37 publications

(44 reference statements)

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“…Basal progenitors may generate projection neurons for all cortical layers (29). Nevertheless, several observations suggest that they give rise primarily to supragranular pyramidal cells (30). Such projection neurons, present in altered numbers in LgDel cortex, may fail to elaborate appropriate local and long distance projections.…”

Section: Discussionmentioning

confidence: 99%

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Meechan¹,

Tucker²,

Maynard³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

153

173

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The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5-to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for ''diseases of cortical connectivity'' thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbuminlabeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. psychiatric disease T he neurodevelopmental hypothesis for diseases of cortical connectivity, initially proposed for schizophrenia (1), and later extended to autism spectrum disorders (2), suggests that anomalous cortical development underlies behavioral pathology. Despite inferred relationships between suspect developmental mechanisms, neuroanatomical or functional changes in patients, and postmortem cortical pathology, to our knowledge, there are no known direct links between specific cortical developmental mechanisms and pathogenesis. The near impossibility of prospective analyses in at-risk human fetuses further complicates rigorous evaluation of the hypothesis. Thus, the hypothesis may be more effectively evaluated in animal models of genetic or environmental risk for relevant diseases. In humans, 22q11 deletion/DiGeorge syndrome (22q11DS) confers the highest known genetic risk for schizophrenia (Ϸ30%) (3, 4), increased susceptibility for autism spectrum disorders (Ϸ25%) (5), and vulnerability for additional behavioral and learning disabilities (Ͼ60%) (5). Brain imaging in 22q11DS patients shows consistent anatomical defects, including reduced cortical gray matter and polymicrogyria (6-8), and postmortem analysis indicates cellular pathology associated with developmental defects including periventricular heteropias (9). We found that diminished 22q11 gene dosage in a 22q11DS mouse model compromises specific cortical neural stem cells, basal progenitors, and alters frequency and distribution of cortical projection neurons and GABAergic interneurons. These phenotypes suggest a link between a genomic lesion, altered cortical development, and subsequent changes in cortical circuitry that likely intensify risk for behavioral diso...

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Section: Discussionmentioning

confidence: 99%

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Meechan¹,

Tucker²,

Maynard³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

153

173

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“…3), further corroborating our claim of a premature end of neurogenesis. Several independent studies have so far failed to establish the ability of Tbr2-positive cells to generate glia; thus, Tbr2 is an indicator of neuronal commitment 21,22 . Because gliogenesis in the mouse neocortex starts at E17.5, we documented cell proliferation at this stage by Ki67 immunostaining.…”

Section: Sip1 Controls the Timing Of Glial Precursor Specificationmentioning

confidence: 99%

Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

et al. 2009

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The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.

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“…Immunostaining results showed specificity to developing mouse cerebral cortical tissue (Guillermo Estivill-Torrus), human embryonic stem cells that differentiated into mesoderm (Ludovic Vallier, University of Cambridge), and in adult mouse hippocampal tissue (Hongjun Song Lab). As others have done (Arnold et al, 2008), we use the anti-TBR2 antibody to detect and analyze basal progenitors in NfiB +/+ and NfiB −/− brains throughout cortical development.…”

Section: Tbr2 (Officially Eomes)-mentioning

confidence: 99%

“…Basal progenitors, the second major class of neural progenitors, uniquely express TBR2, a T-box transcription factor (Arnold et al, 2008;Sessa et al, 2008;Kowalczyk et al, 2009). Unlike radial glia, basal progenitors are multipolar, lack apico-basal processes and their cell bodies reside throughout the SVZ.…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor one B regulates neural stem cell differentiation and axonal projection of corticofugal neurons

Betancourt

Katzman

Chen

2013

J of Comparative Neurology

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During development of the cerebral cortex, neural stem cells divide to expand the progenitor pool and generate basal progenitors, outer radial glia and cortical neurons. As these newly born neurons differentiate, they must properly migrate toward their final destination in the cortical plate, project axons to appropriate targets, and develop dendrites. However, a complete understanding of the precise genetic mechanisms regulating these steps is lacking. Here we show that a member of the nuclear factor one (NFI) family of transcription factors, NFIB, is essential for many of these processes in mice. We performed a detailed analysis of NFIB expression during cortical development, and investigated defects in cortical neurogenesis, neuronal migration and differentiation in NfiB −/− brains. We found that NFIB is strongly expressed in radial glia and corticofugal neurons throughout cortical development. However, in NfiB −/− cortices, radial glia failed to generate outer radial glia, subsequently resulting in a loss of late basal progenitors. In addition, corticofugal neurons showed a severe loss of axonal projections, while late-born cortical neurons displayed defects in migration and ectopically expressed the early-born neuronal marker, CTIP2. Furthermore, gene expression analysis, by RNA-sequencing, revealed a misexpression of genes that regulate the cell cycle, neuronal differentiation and migration in NfiB −/− brains. Together these results demonstrate the critical functions of NFIB in regulating cortical development.

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

Cited by 298 publications

References 37 publications

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

Nuclear factor one B regulates neural stem cell differentiation and axonal projection of corticofugal neurons

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