Tbr2 Directs Conversion of Radial Glia into Basal Precursors and Guides Neuronal Amplification by Indirect Neurogenesis in the Developing Neocortex

Sessa, Alessandro; Mao, Chai An; Hadjantonakis, Anna-Katerina; Klein, William H.; Broccoli, Vania

doi:10.1016/j.neuron.2008.09.028

Cited by 354 publications

(383 citation statements)

References 59 publications

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“…To test this hypothesis, cortical sections were subjected to TUNEL assay, to reveal apoptotic cells, and were immunostained in parallel with antibodies recognizing Pax6 (Figure 1b), Tbr2 ( Figure 1c) and Tubb3 (Figures 1b and c) that identify apical progenitors, basal progenitors or postmitotic neurons, respectively. 27 Interestingly, although ∼ 60% of the apoptotic cells were negative for these markers, double positive cells were clearly detected in all cases (Figures 1d-f). However, the frequency of apoptosis in Tubb3-positive cells was much higher than in Pax6-positive or in Tbr2-positive cells (Figure 1g).…”

Section: Resultsmentioning

confidence: 83%

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

et al. 2015

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Cytokinesis, the physical separation of daughter cells at the end of cell cycle, is commonly considered a highly stereotyped phenomenon. However, in some specialized cells this process may involve specific molecular events that are still largely unknown. In mammals, loss of Citron-kinase (CIT-K) leads to massive cytokinesis failure and apoptosis only in neuronal progenitors and in male germ cells, resulting in severe microcephaly and testicular hypoplasia, but the reasons for this specificity are unknown. In this report we show that CIT-K modulates the stability of midbody microtubules and that the expression of tubulin β-III (TUBB3) is crucial for this phenotype. We observed that TUBB3 is expressed in proliferating CNS progenitors, with a pattern correlating with the susceptibility to CIT-K loss. More importantly, depletion of TUBB3 in CIT-K-dependent cells makes them resistant to CIT-K loss, whereas TUBB3 overexpression increases their sensitivity to CIT-K knockdown. The loss of CIT-K leads to a strong decrease in the phosphorylation of S444 on TUBB3, a post-translational modification associated with microtubule stabilization. CIT-K may promote this event by interacting with TUBB3 and by recruiting at the midbody casein kinase-2α (CK2α) that has previously been reported to phosphorylate the S444 residue. Indeed, CK2α is lost from the midbody in CIT-K-depleted cells. Moreover, expression of the nonphosphorylatable TUBB3 mutant S444A induces cytokinesis failure, whereas expression of the phospho-mimetic mutant S444D rescues the cytokinesis failure induced by both CIT-K and CK2α loss. Altogether, our findings reveal that expression of relatively low levels of TUBB3 in mitotic cells can be detrimental for their cytokinesis and underscore the importance of CIT-K in counteracting this event.

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Section: Resultsmentioning

confidence: 83%

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

et al. 2015

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“…Cortical thickness in the RP58 cKO was progressively reduced starting at E15. 5 and was less than half of that of the control cortex at BP2 (Figures 1g-j and Supplementary Figure 2). Thus, analyses of our cKO mutant extend previous findings with a straight KO, 16 and highlight the requirement of RP58 for normal postnatal brain growth.…”

Section: Resultsmentioning

confidence: 97%

“…[1][2][3] INPs divide 1-2 times and only give rise to neurons, with regulation of their number proposed to contribute to cortical expansion. [1][2][3][4][5][6] Molecularly, a sequence of key transcription factors, Pax6-4Ngn2-4Tbr2-4NeuroD1-4Tbr1, promotes cortical neurogenesis. 7 Among these, Ngn2 is required for transition from early Pax6 þ radial glia to Tbr2 þ INPs, as well as for expansion of INPs, whereas NeuroD1 is expressed in INPs and early-differentiating neurons.…”

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confidence: 99%

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

et al. 2011

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Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects. Using a novel conditional RP58 allele here we show that its CNS-specific loss yields a novel postnatal phenotype: microencephaly, agenesis of the corpus callosum and cerebellar hypoplasia that resembles the chr1qter deletion microcephaly syndrome in human. RP58 mutant brains maintain precursor pools but have reduced neuronal and increased glial differentiation. Well-timed downregulation of pax6, ngn2 and neuroD1 depends on RP58 mediated transcriptional repression, ngn2 and neuroD1 being direct targets. Thus, RP58 may act to favor neuronal differentiation and brain growth by coherently repressing multiple proneurogenic genes in a timely manner. The cerebral cortex undergoes rapid expansion during embryogenesis, when neuronal layers are formed. Two main types of precursors exist in the developing neocortex: multipotent radial glial stem/progenitor cells (RGCs) in the ventricular zone (VZ) and derived intermediate neurogenic progenitors (INPs) in the subventricular zone (SVZ). 1-3 INPs divide 1-2 times and only give rise to neurons, with regulation of their number proposed to contribute to cortical expansion. [1][2][3][4][5][6] Molecularly, a sequence of key transcription factors, Pax6-4Ngn2-4Tbr2-4NeuroD1-4Tbr1, promotes cortical neurogenesis. 7 Among these, Ngn2 is required for transition from early Pax6 þ radial glia to Tbr2 þ INPs, as well as for expansion of INPs, whereas NeuroD1 is expressed in INPs and early-differentiating neurons. 7,8 How their sequential timed expression is regulated to promote the development of normal-sized cortices is unknown.The development of human microcephaly likely results from abnormal cortical precursor behavior. Interestingly, deletion of the distal end of human chromosome-1q is linked to microcephaly with agenesis of the corpus callosum (e.g. 9-11), and a critical region contains only a handful of genes, including RP58. 9-12 RP58, also known as ZNF238, 13 encodes a transcription factor with a BTB/POZ and four zincfinger domains 14 that is highly conserved (495%) between humans and mice, suggesting conserved functions.Previous work has shown that RP58 is expressed in mouse brain precursors and neurons, 15 and that its complete loss leads to defects in cortical and hippocampal development. 16 Critically, perinatal death of conventional knockout (KO) mice 16 precludes analyses in postnatal stages. Furthermore, the reported defects in cell-cycle exit, and in Pax6 þ and Tbr2 þ populations, were deduced from analyses at late corticogenesis stages after embryonic day (E) 16.5, precluding any conclusions on early defects and not provi...

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“…3e-g). Since the overexpression of Tbr2 in RG increases BP number and Cxcl12 expression 4 , we next assessed whether the overexpression of Tbr2 might trigger microglia accumulation into the VZ/SVZ. We electroporated plasmids encoding Tbr2 and GFP at E14.5, and brains were probed for Cxcl12 2 days later, at E16.5.…”

Section: Resultsmentioning

confidence: 99%

“…BPs originate from asymmetric cell divisions of RG and are fated to differentiate into cortical plate excitatory neurons 2,3 and to regulate inhibitory neurons' migration through the release of the chemokine Cxcl12. The downregulation of the transcription factor Tbr2 impairs BP generation and induces a significant reduction of Cxcl12 into the SVZ 4 that, in turn, affects inhibitory neurons migration 5,6 . Accordingly, inhibitory neurons lacking CxcR4-that is one of the two Cxcl12 receptors 7,8 -are impaired in their homing into the cerebral cortex 9 , while CxcR7 is involved in the regulation of CxcR4 protein levels 10 .…”

mentioning

confidence: 99%

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

Arnò¹,

Grassivaro²,

Rossi³

et al. 2014

Nat Commun

187

173

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Microglia are observed in the early developing forebrain and contribute to the regulation of neurogenesis through still unravelled mechanisms. In the developing cerebral cortex, microglia cluster in the ventricular/subventricular zone (VZ/SVZ), a region containing Cxcl12-expressing basal progenitors (BPs). Here we show that the ablation of BP as well as genetic loss of Cxcl12 affect microglia recruitment into the SVZ. Ectopic Cxcl12 expression or pharmacological blockage of CxcR4 further supports that Cxcl12/CxcR4 signalling is involved in microglial recruitment during cortical development. Furthermore, we found that cell death in the developing forebrain triggers microglial proliferation and that this is mediated by the release of macrophage migration inhibitory factor (MIF). Finally, we show that the depletion of microglia in mice lacking receptor for colony-stimulating factor-1 (Csf-1R) reduces BPs into the cerebral cortex.

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Tbr2 Directs Conversion of Radial Glia into Basal Precursors and Guides Neuronal Amplification by Indirect Neurogenesis in the Developing Neocortex

Cited by 354 publications

References 59 publications

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

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