Molecular Control of Mammalian Neuronal Production

Overview

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

What regulates brain size? When it comes to brains, size matters. Humans possess an impressive repertoire of mental skills such as the abilities to read, write, and solve intricate problems. These skills are made possible by the cerebral cortex, the thin, layered sheet of neurons on the surface of the brain that underlies our most complex cognitive abilities. Although all mammals have cerebral cortices, the cerebral cortex in primates, especially that of humans, has undergone a vast expansion in size during evolution, and the increase in the size of the cerebral cortex is thought to underlie the growth of intellectual capacity. Despite many hypotheses about how brain size is regulated, few have been tested experimentally.

We are interested in the factors that regulate the production and differentiation of neurons in the brain. The increased size of the cerebral cortex during evolution results primarily from a disproportional expansion of its surface area, with the appearance of folds of the cortical surface (with hills known as gyri and intervening valleys called sulci) providing a means to increase the total cortical area in a given skull volume. This expansion of the length and breadth of cerebral cortex is not accompanied by a comparable increase in cortical thickness; in fact, the one thousand fold increase in cortical surface area between human and mouse is only accompanied by an approximate two fold increase in cortical thickness.

The cerebral cortex is organized into interconnected groups of radially-organized neurons called columns, and the expansion of the cortex appears to result from increases in the number of columns rather than increases in individual column size. These observations have led to the proposal that increases in the number of columns result from a corresponding increased number of progenitor cells. As a result, minor changes in the relative production of progenitors and neurons could produce dramatic increases in cortical surface area. We are using a variety of approaches to try to identify the factors that control the production of neural progenitors and neurons during brain development.

Research Summary

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?