regulation of neural stem cells and development of the mammalian neocortex
	Weimin Zhong, Ph.D. Associate Professor of Molecular, Cellular and Developmental Biology Yale University, KBT 616B PO Box 208103, 266 Whitney Ave New Haven, CT 06520 Email: weimin.zhong@yale.edu Phone: (203) 432-9233/ (203) 432-3035 Ph.D. The Rockefeller University 1993

Asymmetric localization of the moue Numb protein in dividing neural progenitor cells.

numblike expression in an E12.5 mouse embryo

We are interested in the molecular and cellular mechanisms that govern the behavior of stem cells, in particular how they balance the needs of self-renewal and differentiation during mammalian organogenesis and tissue maintenance. Current research uses neurogenesis in mice as a model system to study how neural stem (progenitor) cells are maintained and how neuronal diversity is generated in the mammalian nervous system. We are examining whether Numb-mediated asymmetric cell division represents a mechanism that is shared by stem cells in many tissues for their progeny to choose between self-renewal and differentiation. By elucidating how this mechanism acts together with other cell-intrinsic and cell-extrinsic cues to form organs and maintain tissue homeostasis, we hope to understand the fundamental biology of stem cells and provide insights for their therapeutic use in repairing or replacing damaged tissues.

Stem cells, whether of embryonic or adult origin, are defined by the ability to produce more stem cells (self-renew) and the potential to generate differentiated offspring for carrying out tissue function. For stem cells involved in organogenesis and tissue maintenance, there is also an essential need to ensure a proper balance between self-renewal and differentiation, since a failure in either task will lead to organ malformation and tissue malfunction. How this is accomplished at the molecular and cellular level, however, remains poorly understood in mammals. Conceptually, stem cells can simultaneously self-renew and differentiate by dividing asymmetrically to produce one daughter cell that remains as a stem cell and another that differentiates. Stem cells, however, may also need to divide symmetrically to produce two stem cells, which can quickly expand their population when responding to a tissue injury, or to generate two differentiated cells, when large numbers of stem cells are no longer necessary towards the end of organogenesis and tissue repair. In other words, understanding the division patterns of stem cells – particularly how they are regulated under normal and pathological conditions – may facilitate a key goal of stem-cell research, which is to repair or replace damaged tissues by introducing exogenous stem cells or expanding endogenous populations.

Asymmetric cell division, a process by which a cell divides to produce two different daughter cells, is widely used by invertebrates to generate cellular diversity during development. In Drosophila, the Numb protein enables the two daughter cells to adopt different fates after such divisions by segregating primarily to one daughter cell. To examine the importance of asymmetric cell division in mammalian development, we identified two mouse numb genes, m-numb (Numb) and numblike (Numbl or nbl). We postulated that mammalian neural progenitor cells, which behave like stem cells during neurogenesis, balance self-renewal and differentiation by segregating Numb proteins asymmetrically to produce a daughter progenitor cell and a neuron. Through a series of loss- and gain-of-function studies in mice, we show that Numb and Numbl are redundant but essential for embryogenesis and that asymmetric Numb segregation and, therefore, asymmetric cell division are indeed essential for neural progenitor cells to balance the competing needs of self-renewal and differentiation during neurogenesis. Our studies further reveal a novel cellular mechanism that uses Golgi fragmentation and reconstitution, through changes in the subcellular distribution of an essential Numb partner, the ACBD3 protein, to coordinate cell-cycle progression and cell-fate specification during an asymmetric cell division.

Current research is focused on three areas:

(1) Probing the behavior of stem cells by changing their patterns of division
We have generated a set of unique mouse strains in which the division patterns of stem cells in various tissues can be differentially manipulated. We will use these mice to examine how stem cells behave in their microenvironment (niche) under normal and pathological conditions in the nervous system and other tissues. By forcing stem cells to deviate from their normal patterns of division, we intend to identify key regulators of stem cells using molecular and genetic tools.

(2) Examining how cell fates are assigned to maintain tissue homeostasis
To maintain tissue homeostasis, stem cells have to generate differentiated cells of specific types, in correct numbers and at precise times. As a first step to understand how this is accomplished, we will combine studies using mice and Drosophila to elucidate the signaling pathway that enables Numb and ACBD3 proteins to specify distinct daughter cell fates during an asymmetric division. We will also examine whether the process of Golgi fragmentation and reconstitution is a general mechanism for stem cells to coordinate cellular signaling and cell-cycle progression.

(3) Using embryonic stem (ES) cells to probe human developmental mechanisms
We intend to examine whether the findings from our mouse studies are applicable to humans by determining whether Numb-mediated asymmetric cell divisions, as well as the signaling pathways that regulate stem-cell behavior, are used by human ES cells when they are induced to undergo neurogenesis in culture.

Selected Publications

Zhou, Y., Atkins, J.A., Rompani, S.B., Bancescu, D.L., Petersen, P.H., Tang, H., Zou, K., Stewart, S.B., & Zhong, W. (2007) The mammalian Golgi controls Numb signaling in asymmetric cell division by releasing ACBD3 during mitosis. Cell 129:163-178.

Petersen, P.H., Tang, H., Zou, K., & Zhong, W. (2006) The enigma of the Numb-Notch relationship during mammalian embryogenesis. Developmental Neuroscience 28:156-168.

Tang, H.T., Rompani, S.B., Atkins, J.B., Zhou, Y., Osterwalder, T., & Zhong, W. (2005) Numb proteins specify asymmetric cell fates via an endocytosis and proteasome independent pathway. Molecular and Cellular Biology 25:2899-2909.

Petersen, P.H., Zou, K., Krauss, S., & Zhong, W. (2004) Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Nature Neuroscience 7:803-811.

Zhong, W. (2003) Diversifying neural cells through order of birth and asymmetry of division. Neuron 37:11-14 (minireview).

Petersen, P.H., Zou, K., Hwang, J.K., Jan, Y.N., & Zhong, W. (2002) Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature 419:929-934.

Zhong, W., Jiang, M.-M., Weinmaster, G., Jan, L.Y., & Jan, Y.N. (1997) Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Development 124:1887-1897.

			Loss of mouse numb and numblike causes premature depletion of neural progenitor cells (in blue) in the developing (E10.25) spinal cord due to overproduction of neurons (in green), which subsequently undergo programmed cell death (in red).

			Hes5 expression in the brain of an E15.5 mouse embryo mutant for numb and numblike, showing premature depletion of neural progenitor cells specifically in the dorsal forebrain, where the two genes had been inactivated.

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