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

Institut National d'Hygiène du Maroc, Rabat, Rabat-Salé-Zemmour-Zaër, Morocco
Nature Genetics (Impact Factor: 29.35). 05/2007; 39(4):454-6. DOI: 10.1038/ng1993
Source: PubMed


Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.

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    • "PMG, microcephaly and agenesis of the corpus callosum are described in inactivation of the T-box transcription factor gene EOMES [52]. EOMES codes a transcription factor which influences regional gene expression and is involved in implementing regional identity in the cortex [51]. "
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    ABSTRACT: Polymicrogyria (PMG) is a complex cortical malformation which has so far defied any mechanistic or genetic explanation. Adopting a broad definition of an abnormally folded or festooned cerebral cortical neuronal ribbon, this review addresses the literature on PMG and the mechanisms of its development, as derived from the neuropathological study of many cases of human PMG, a large proportion in fetal life. This reveals the several processes which appear to be involved in the early stages of formation of polymicrogyric cortex. The most consistent feature of developing PMG is disruption of the brain surface with pial defects, over-migration of cells, thickening and reduplication of the pial collagen layers and increased leptomeningeal vascularity. Evidence from animal models is consistent with our observations and supports the notion that disturbance in the formation of the leptomeninges or loss of their normal signalling functions are potent contributors to cortical malformation. Other mechanisms which may lead to PMG include premature folding of the neuronal band, abnormal fusion of adjacent gyri and laminar necrosis of the developing cortex. The observation of PMG in association with other and better understood forms of brain malformation, such as cobblestone cortex, suggests mechanistic pathways for some forms of PMG. The role of altered physical properties of the thickened leptomeninges in exerting mechanical constraints on the developing cortex is also considered. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0080-3) contains supplementary material, which is available to authorized users.
    07/2014; 2(1):80. DOI:10.1186/PREACCEPT-1342027701333555
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    • "PMG has been associated with different chromosomal abnormalities (Leventer et al., 2008; Dobyns et al., 2008 Jaglin et al., 2009; Barkovich, 2010). PMG has also been related to mutations of several genes, such as SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1, and COLI8A1 (Glaser et al., 1994; Sertié et al., 2000; Brooks et al., 2005; Aligianis et al., 2005; Roll et al., 2006; Baala et al., 2007). In addition, copy number variations have been described (Guerrini and Parrini, 2010). "
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    ABSTRACT: Aim: We retrospectively analysed the electroclinical features, treatment, and outcome in patients with unilateral polymicrogyria (PMG), focussing on epileptic syndrome with or without encephalopathy, with status epilepticus during sleep (ESES) or continuous spikes and waves during slow sleep (CSWS) syndrome. Methods: From June 1990 to December 2012, 39 males and 27 females, aged 5-26 years, were studied. We did not include patients with bilateral PMG or cases with unilateral PMG associated with other cerebral lesions. The mean follow-up period was 12 years (range: 3-22 years). Results: Mean age at epilepsy onset was 6.5 years. Focal motor seizures occurred in all cases and 25 had secondary generalised seizures. Six patients also had complex focal seizures. Interictal EEG recordings showed focal spikes in all cases. For 43 of 53 patients with epilepsy, aged 2-9.5 years, the electroclinical features changed. An increase in frequency of focal motor seizures was reported in 20 patients, negative myoclonus occurred in 32 patients, atypical absences in 25 patients, and positive myoclonus in 19 patients. All patients had a continuous symmetric or asymmetric pattern of spike-wave activity during slow-wave sleep. Conclusion: For patients presenting with congenital hemiparesis, negative or positive myoclonus, and absences and focal motor seizures with ESES/CSWS, unilateral PMG should be considered. Brain MRI is mandatory to confirm this cortical malformation. The most commonly used treatments were clobazam, ethosuximide, and sulthiame, alone or in combination. For refractory cases, high-dose steroids were administered and surgery was performed in two patients. Outcome was relatively benign.
    Epileptic disorders: international epilepsy journal with videotape 11/2013; 15(4). DOI:10.1684/epd.2013.0612 · 0.95 Impact Factor
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    • "In this study fluorescence activated cell (FAC) sorting was used to purify neurons of the excitatory cortical lineage, from which RNA was isolated for transcriptional profiling. We focused on the neuronal lineage that expresses Eomes (Tbr2), a transcription factor that is expressed by intermediate precursor cells [19] and has been genetically linked to microcephaly in mouse [20] and human [21]. The target neurons were acutely dissociated at E14.5 from a reporter transgenic mouse (Eomes::eGFP)Gsat in which immature neurons of the excitatory lineage express eGFP [22]. "
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    ABSTRACT: Background Cortical neurons display dynamic patterns of gene expression during the coincident processes of differentiation and migration through the developing cerebrum. To identify genes selectively expressed by the Eomes + (Tbr2) lineage of excitatory cortical neurons, GFP-expressing cells from Tg(Eomes::eGFP) Gsat embryos were isolated to > 99% purity and profiled. Results We report the identification, validation and spatial grouping of genes selectively expressed within the Eomes + cortical excitatory neuron lineage during early cortical development. In these neurons 475 genes were expressed ≥ 3-fold, and 534 genes ≤ 3-fold, compared to the reference population of neuronal precursors. Of the up-regulated genes, 328 were represented at the Genepaint in situ hybridization database and 317 (97%) were validated as having spatial expression patterns consistent with the lineage of differentiating excitatory neurons. A novel approach for quantifying in situ hybridization patterns (QISP) across the cerebral wall was developed that allowed the hierarchical clustering of genes into putative co-regulated groups. Forty four candidate genes were identified that show spatial expression with Intermediate Precursor Cells, 49 candidate genes show spatial expression with Multipolar Neurons, while the remaining 224 genes achieved peak expression in the developing cortical plate. Conclusions This analysis of differentiating excitatory neurons revealed the expression patterns of 37 transcription factors, many chemotropic signaling molecules (including the Semaphorin, Netrin and Slit signaling pathways), and unexpected evidence for non-canonical neurotransmitter signaling and changes in mechanisms of glucose metabolism. Over half of the 317 identified genes are associated with neuronal disease making these findings a valuable resource for studies of neurological development and disease.
    BMC Neuroscience 08/2012; 13(1):90. DOI:10.1186/1471-2202-13-90 · 2.67 Impact Factor
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