Anjen Chenn, MD, PhD Assistant Professor Pathology Developmental Neurobiology: Regulation of Cell Fate and Cell Proliferation in the Mammalian CNS Curricula: Cancer Biology Cell Biology  Developmental Biology Molecular Biology and Genetics Neurobiology E-mail:   achenn@northwestern.edu

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Our major research interest is understanding the factors that control cell proliferation and differentiation in the developing mammalian central nervous system.

A fundamental question in developmental neurobiology is how an initially homogenous population of precursor cells expands and gives rise to the vast diversity of cells that comprise the mature brain. Understanding the control of cell division and the relationship between proliferation and differentiation has profound implications not only for developmental neuroscience, but also for disorders of the human nervous system. Problems in proliferation have been implicated in microcephaly (small brain), mental retardation, and schizophrenia, while misregulated proliferation can lead to cancer, cortical malformations, and epilepsy. Furthermore, an understanding of neuronal production from neural stem cells may offer potential therapy for neurodegenerative disease.

Asymmetric Divisions and Neuronal Production
Neurons in the mammalian central nervous system are generated from progenitor cells lining the lumen of the neural tube. Using time-lapse microscopy of dividing cells in slices of developing cerebral cortex, we have shown that cleavage orientation predicts the fates of daughter cells. Vertical cleavages produce behaviorally and morphologically identical daughters that resemble precursor cells; these symmetric divisions may serve to expand or maintain the progenitor pool. In contrast, horizontally dividing cells produce basal daughters that behave like young migratory neurons and apical daughters that remain within the proliferative zone. How the orientation of cell divisions is regulated during development remains unknown

Epithelial Organization and Cell Fate Determination
Although the mechanisms that regulate cell proliferation during neural development are poorly understood, studies in other tissues suggest that loss of normal cell polarity and tissue architecture play crucial regulatory roles in cell proliferation and cancer. Our most recent work suggests that beta catenin, an integral component of the adherens junction, can regulate cell cycle re-entry and differentiation in the developing mammalian brain. Transgenic mice expressing a truncated, stabilized form of beta catenin develop massively enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. Understanding the biology of epithelial organization can lend insight onto the regulation of proliferation during neural development and ultimately reveal mechanisms underlying developmental brain disorders and tumors in the central nervous system.

Publications:

Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cereb Cortex. 2003 Jun;13(6):599-606. PMID: 12764034

Chenn A. Eppendorf & Science Prize. Essays on science and society. Making a bigger brain by regulating cell cycle exit. Science. 2002 Oct 25;298(5594):766-7. PMID: 12399574

Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. 2002 Jul 19;297(5580):365-9.

Chenn, A., Levin, M.E., McConnell, S.K. Restricted Cerebral Cortex Expression of a Candidate G-protein Coupled Receptor. J. Neurobiol. 2001; 46(3): p. 167-77.

Chenn A, Walsh CA. Perspectives: neurobiology. Cranking it up a notch. Science 1999 Oct 22;286(5440):689-90.

Chenn, A., Zhang, Y.A., Chang, B.T., McConnell, S.K. Intrinsic polarity of mammalian neuroepithelial cells. Mol. Cell. Neurosci. 1998; 11(4): 183-93.

O'Rourke, N.A., Chenn, A., McConnell, S.K. Postmitoitc neurons migrate tangentially in the cortical ventricular zone. Development 1997; 124, 997-1005.

Chenn, A. and McConnell, S.K. Cleavage orientation and the asymmetric inheritance of Notch 1 immunoreactivity in mammalian neurogenesis. Cell 1995; 82, 631-641.