The cerebral cortex is the most complex structure in our brain and the seat of consciousness, emotion, motor control and language. In order to fulfill these functions, it is composed of a diverse array of nerve cells, called cortical neurons, which are affected by many neurological and neuropsychiatric diseases.
Work from a research team led by Pierre Vanderhaeghen (Université libre de Bruxelles (ULB), WELBIO investigator at the Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM -- Faculty of Medicine) and ULB Neuroscience Institute (UNI)) opens new perspectives on brain development and stem cell neurobiology by discovering a gene called BCL6 as a key factor in the generation of cortical neurons during embryonic brain development.
This study is published online Nov. 18 in Nature Neuroscience.
Drs Luca Tiberi and Jelle van den Ameele (FNRS Fellows at IRIBHM, ULB), identified BCL6 by searching for factors that can modulate the production of nerve cells in a model of neural differentiation from mouse embryonic stem cells. They found that overexpression of BCL6 resulted in a massive transformation of neural stem cells into cortical neurons that were well differentiated and functional. This discovery was surprising because BCL6 is in fact a well known oncogene, responsible for various blood cell cancers called lymphomas. However, nothing was known about this gene in brain development. To verify their intriguing observations, the scientists then examined a transgenic mouse model where the BCL6 gene was disrupted. They found that in these mutant mice, the cerebral cortex was significantly smaller and contained less nerve cells. These data thus indicate that BCL6 is actually required during normal brain development for the proper production of cortical neurons. They went on to elucidate the underlying molecular mechanisms and showed that BCL6 acts together with a gene called Sirt1 to repress actors of the Notch pathway that are involved in the self-renewal of neural stem cells. This repression phenomenon is "epigenetic" and drives neural stem cells irreversibly towards differentiation into cortical neurons.
This basic work opens many questions and perspectives, not only for developmental and stem cell neurobiology, but also for cancer biology. Firstly, it identifies a key factor for the production of cortical nerve cells, some of the most important cells in our brain that are also frequently affected by neurological and neuropsychiatric diseases. Secondly, it elucidates a novel molecular mechanism of differentiation, with important implications for our general understanding of what controls the differentiation vs. self-renewal of neural stem cells. Finally, it brings together three major players involved in a myriad of normal and pathological processes: BCL6, an oncogene responsible for blood cell cancer; Sirt1, involved in aging, Alzheimer's disease, metabolism and diabetes; and the Notch pathway, crucial for many processes like brain and heart development or oncogenesis. These genes were not previously shown to interact with each other but might well do in any of these contexts, thus opening a new door to a better understanding of the biology and pathology and the potential development of new therapies.
This work was funded thanks to support of the Fonds National de la Recherche Scientifique, the Fondation Médicale Reine Elisabeth, the Walloon Region (WELBIO et Programme d'Excellence CIBLES), Belgian Federal Funds (IUAP/SSTC), The Foundation Clerdent, The Foundation de Spoelberch, and European Marie Curie et EMBO Fellowships.
- Luca Tiberi, Jelle van den Ameele, Jordane Dimidschstein, Julie Piccirilli, David Gall, Adèle Herpoel, Angéline Bilheu, Jerome Bonnefont, Michelina Iacovino, Michael Kyba, Tristan Bouschet, Pierre Vanderhaeghen. BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets. Nature Neuroscience, 2012; DOI: 10.1038/nn.3264
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