Research SummaryA 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.
How does it all fit together?
Does unregulated cell proliferation cause epithelial disruption or does epithelial disruption lead to unregulated cell proliferation? Do proteins that regulate epithelial structure regulate mitotic orientation?