Verslag – Rapport – Bericht – Report - GSKE - FMRE

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Dr. Pierre Vanderhaeghen, PhD Institute of Interdisciplinary Research (IRIBHN) ULB, Campus Erasme 808, Route de Lennik B-1070 Brussels Tel.: +32 2 555 41 86 Fax: +32 2 555 46 55 pvdhaegh@ulb.ac.be 120 Verslag – Rapport – Report 2012
From stem cells to cortical networks State of the Art / Objectives. The cerebral cortex is one of the most complex and important structures in our brain. It contains dozens of different subtypes of neurons that are distributed into specific layers and areas, which allow efficient control of motor functions, sensory responses, as well as higher cognitive functions including language (Tiberi et al., 2012b). The understanding of the mechanisms that generate this neuronal diversity and cortical cell-type specific properties could be instrumental to understand better human neurodevelopmental disorders such as mental retardation, autism and some forms of epilepsy. In addition, the ability to (re)specify cortical neurons in a controlled way could have a major impact for the rational design of brain repair strategies, to model its diseases, and for pharmaceutical screens. We previously uncovered an intrinsic pathway of cortical neurogenesis, whereby mouse embryonic stem (mES) cells efficiently generate neurons that share most molecular, cellular and functional landmarks of pyramidal neurons of the cerebral cortex (Gaspard et al., 2009; Gaspard et al., 2008). This model opens new opportunities to study corticogenesis and its disorders. Here we have followed a multidisciplinary research programme combining developmental neurobiology and pluripotent stem cell technology, centered on the mechanisms of cortical development in health and disease. We focused on three main objectives: 1. Understanding the mechanisms of specification of cortical neurons. 2. Linking development and evolution of the human cortex. 3. Exploring new ways to repair the diseased cortex. Results 1 Understanding the mechanisms of specification of cortical neurons. Using our model of corticogenesis from mouse ES cells, we have performed a gain of function screen aimed at identifying novel transcriptional programmes involved in cortical neurogenesis. About 20 transcription factors known to be expressed in the developing cortex but without a well characterized function, were overexpressed transiently during in vitro cortical neurogenesis, using in lab-generated ESC lines allowing inducible gene expression upon doxycyclin (Dox) addition (Pietri et al., 2012; van den Ameele et al., 2012). Among the genes tested, the BCL6 B cell oncogene (Ye et al., 1997; Ye et al., 1993) stood up markedly as a potent proneurogenic factor, that triggers the differentiation of cortical progenitors into pyramidal neurons (Tiberi et al., 2012a). To validate these findings physiologically, we tested for the requirement of BCL6 during normal in vivo cortical neurogenesis, using BCL6 knock-out mice. This revealed striking defects in cell cycle exit of neural progenitors and impaired production of pyramidal neurons following BCL6 gene disruption. These complementary approaches thus lead to the important conclusion that BCL6 is necessary and sufficient to promote the generation of cortical pyramidal neurons. We then seeked for the molecular mechanism by which Bcl6 controls cortical neurogenesis, and found Verslag – Rapport – Report 2012 121
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mRNA metabolism at synapses and spi
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eIF4E upon DHPG stimulation, but Ra
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Role of DMRT transcription factors
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Developmental origin of multiple de
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additional experiments, which meanw
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Characterization of Human Sleep/Wak
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candidate-based approach with a pro
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