Weimin Zhong, PhD
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Research Summary
My laboratory studies the molecular and cellular mechanisms governing how stem cells balance the competing needs of self-renewal and differentiation during mammalian organogenesis and tissue maintenance. We use the mammalian Numb proteins, Numb and Numblike (Numbl), as entry point, and neurogenesis in the developing neocortex and mammary gland development in mice as model systems, to probe the contribution of two modes of cell division – symmetric vs. asymmetric – in regulating stem cell behavior, in particular how changes in cell division pattern affect organ development, tissue regeneration and tumor formation, as part of an effort to achieve a key goal of stem-cell research to repair tissues and organs damaged by disease, injury or aging.
Extensive Research Description
We seek to understand why stem cells in mammals cannot repair damages that go beyond the normal wear and tear, even though many mammalian tissues contain stem cells capable of producing differentiated cells to repair normal wears and tears to maintain tissue function throughout life. We hypothesize that multiple factors – through independent molecular pathways that regulate both the number and the temporal competence of stem cells – place fundamental constrains on their ability to repair tissue damages. Current research combines studies using Drosophila and mice to identify molecular components that specify the fates, count the number and regulate the competence of neural and other stem cells. We believe our studies will provide novel insights regarding the biology of stem cells, their therapeutic use in regenerative medicine and how cancers and neurodegenerative diseases like ALS and dementia arise.
Stem cells, whether of embryonic or adult origin, are defined by the abilityto 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 is a process by which a cell divides to produce two different daughter cells. Such divisions are widely used from invertebrates to mammals to generate cellular diversity during development and for stem cells to balance self-renewal and differentiation. In Drosophila, the Numb protein enables the two daughter cells to adopt different fates at birth after such divisions by localizing to only one side of a dividing precursor cell. 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 localization in dividing neural stem cells is essential for generating the central nervous system. Our studies further reveal a novel cellular mechanism that uses Golgi fragmentation and reconstitution during mitosis, 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.
(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 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, ACBD3 and other partners to specify distinct daughter cell fates at birth during an asymmetric division, in particular how cellular signaling, epigenetic regulation and cell-cycle progression are coordinated.
(3) Examining how stem cells are regulated temporally
In the developing mammalian neocortex, neural stem cells change competence over time to sequentially produce six layers of functionally distinct neurons. Through a collaboration with scientists at Peking Union Medical College, we show microRNAs (miRNAs) are dispensable for stem-cell self-renewal and neuron production but essential for timing neocortical layer formation and specifying laminar fates in mice. We are examining how miRNAs determine temporal fates during neocortical neurogenesis.
(4) 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.
Coauthors
Selected Publications
- Cardiomyocyte orientation modulated by the Numb family proteins–N-cadherin axis is essential for ventricular wall morphogenesisMiao L, Li J, Li J, Lu Y, Shieh D, Mazurkiewicz JE, Barroso M, Schwarz JJ, Xin HB, Singer HA, Vincent PA, Zhong W, Radice GL, Wan LQ, Fan ZC, Huang G, Wu M. Cardiomyocyte orientation modulated by the Numb family proteins–N-cadherin axis is essential for ventricular wall morphogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 15560-15569. PMID: 31300538, PMCID: PMC6681736, DOI: 10.1073/pnas.1904684116.
- Opposing Gradients of MicroRNA Expression Temporally Pattern Layer Formation in the Developing NeocortexShu P, Wu C, Ruan X, Liu W, Hou L, Fu H, Wang M, Liu C, Zeng Y, Chen P, Yin B, Yuan J, Qiang B, Peng X, Zhong W. Opposing Gradients of MicroRNA Expression Temporally Pattern Layer Formation in the Developing Neocortex. Developmental Cell 2019, 49: 764-785.e4. PMID: 31080058, DOI: 10.1016/j.devcel.2019.04.017.
- A new partnership for an impactful futureZhong W, Wang DC. A new partnership for an impactful future. Science China Life Sciences 2016, 59: 1-2. PMID: 26833309, DOI: 10.1007/s11427-016-5014-9.
- Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitorsShenje LT, Andersen P, Uosaki H, Fernandez L, Rainer PP, Cho GS, Lee DI, Zhong W, Harvey RP, Kass DA, Kwon C. Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors. ELife 2014, 3: e02164. PMID: 24843018, PMCID: PMC4007206, DOI: 10.7554/elife.02164.
- Numb family proteins are essential for cardiac morphogenesis and progenitor differentiationZhao C, Guo H, Li J, Myint T, Pittman W, Yang L, Zhong W, Schwartz RJ, Schwarz JJ, Singer HA, Tallquist MD, Wu M. Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation. Development 2013, 141: 281-295. PMID: 24335256, PMCID: PMC3879810, DOI: 10.1242/dev.093690.
- Olympics: Some facts about Ye Shiwen's swim.Zhong W, Wu H, Li L. Olympics: Some facts about Ye Shiwen's swim. Nature 2012, 488: 459. PMID: 22914156, DOI: 10.1038/488459a.
- Membrane compartments and organelles: new tricks by old dogs and new kids on the blockNiwa M, Zhong W. Membrane compartments and organelles: new tricks by old dogs and new kids on the block. Current Opinion In Cell Biology 2012, 24: 449-452. PMID: 22909897, DOI: 10.1016/j.ceb.2012.08.001.
- Golgi during DevelopmentZhong W. Golgi during Development. Cold Spring Harbor Perspectives In Biology 2011, 3: a005363. PMID: 21768608, PMCID: PMC3181030, DOI: 10.1101/cshperspect.a005363.
- New University Plan Skips Crucial StepsZhong W. New University Plan Skips Crucial Steps. Science 2011, 332: 662-663. PMID: 21551046, DOI: 10.1126/science.332.6030.662-b.
- Going Nuclear Is Again a Winning (Wnt) StrategyZhong W. Going Nuclear Is Again a Winning (Wnt) Strategy. Developmental Cell 2008, 15: 635-636. PMID: 19000826, DOI: 10.1016/j.devcel.2008.10.012.
- Timing cell-fate determination during asymmetric cell divisionsZhong W. Timing cell-fate determination during asymmetric cell divisions. Current Opinion In Neurobiology 2008, 18: 472-478. PMID: 18983918, PMCID: PMC2609754, DOI: 10.1016/j.conb.2008.10.005.
- Neurogenesis and asymmetric cell divisionZhong W, Chia W. Neurogenesis and asymmetric cell division. Current Opinion In Neurobiology 2008, 18: 4-11. PMID: 18513950, DOI: 10.1016/j.conb.2008.05.002.
- The Mammalian Golgi Regulates Numb Signaling in Asymmetric Cell Division by Releasing ACBD3 during MitosisZhou Y, Atkins JB, Rompani SB, Bancescu DL, Petersen PH, Tang H, Zou K, Stewart SB, Zhong W. The Mammalian Golgi Regulates Numb Signaling in Asymmetric Cell Division by Releasing ACBD3 during Mitosis. Cell 2007, 129: 163-178. PMID: 17418793, DOI: 10.1016/j.cell.2007.02.037.
- The Enigma of the Numb-Notch Relationship during Mammalian EmbryogenesisPetersen PH, Tang H, Zou K, Zhong W. The Enigma of the Numb-Notch Relationship during Mammalian Embryogenesis. Developmental Neuroscience 2006, 28: 156-168. PMID: 16508312, DOI: 10.1159/000090761.
- Numb Proteins Specify Asymmetric Cell Fates via an Endocytosis- and Proteasome-Independent PathwayTang H, Rompani SB, Atkins JB, Zhou Y, Osterwalder T, Zhong W. Numb Proteins Specify Asymmetric Cell Fates via an Endocytosis- and Proteasome-Independent Pathway. Molecular And Cellular Biology 2005, 25: 2899-2909. PMID: 15798180, PMCID: PMC1069617, DOI: 10.1128/mcb.25.8.2899-2909.2005.
- Effects of canonical Wnt signaling on dorso-ventral specification of the mouse telencephalonBackman M, Machon O, Mygland L, van den Bout CJ, Zhong W, Taketo MM, Krauss S. Effects of canonical Wnt signaling on dorso-ventral specification of the mouse telencephalon. Developmental Biology 2005, 279: 155-168. PMID: 15708565, DOI: 10.1016/j.ydbio.2004.12.010.
- The Notch Regulator Numb Links the Notch and TCR Signaling PathwaysAnderson AC, Kitchens EA, Chan SW, St. Hill C, Jan YN, Zhong W, Robey EA. The Notch Regulator Numb Links the Notch and TCR Signaling Pathways. The Journal Of Immunology 2005, 174: 890-897. PMID: 15634911, DOI: 10.4049/jimmunol.174.2.890.
- Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborizationHuang EJ, Li H, Tang AA, Wiggins AK, Neve RL, Zhong W, Jan LY, Jan YN. Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization. Genes & Development 2004, 19: 138-151. PMID: 15598981, PMCID: PMC540232, DOI: 10.1101/gad.1246005.
- Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesisPetersen PH, Zou K, Krauss S, Zhong W. Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Nature Neuroscience 2004, 7: 803-811. PMID: 15273690, DOI: 10.1038/nn1289.
- Major Molecular Differences between Mammalian Sexes Are Involved in Drug Metabolism and Renal FunctionRinn JL, Rozowsky JS, Laurenzi IJ, Petersen PH, Zou K, Zhong W, Gerstein M, Snyder M. Major Molecular Differences between Mammalian Sexes Are Involved in Drug Metabolism and Renal Function. Developmental Cell 2004, 6: 791-800. PMID: 15177028, DOI: 10.1016/j.devcel.2004.05.005.
- Nestin promoter/enhancer directs transgene expression to precursors of adult generated periglomerular neuronsBeech RD, Cleary MA, Treloar HB, Eisch AJ, Harrist AV, Zhong W, Greer CA, Duman RS, Picciotto MR. Nestin promoter/enhancer directs transgene expression to precursors of adult generated periglomerular neurons. The Journal Of Comparative Neurology 2004, 475: 128-141. PMID: 15176089, DOI: 10.1002/cne.20179.
- Diversifying Neural Cells through Order of Birth and Asymmetry of DivisionZhong W. Diversifying Neural Cells through Order of Birth and Asymmetry of Division. Neuron 2003, 37: 11-14. PMID: 12526768, DOI: 10.1016/s0896-6273(02)01178-9.
- Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts.Shen Q, Zhong W, Jan YN, Temple S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 2002, 129: 4843-53. PMID: 12361975, DOI: 10.1242/dev.129.20.4843.
- Progenitor cell maintenance requires numb and numblike during mouse neurogenesisPetersen PH, Zou K, Hwang JK, Jan YN, Zhong W. Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature 2002, 419: 929-934. PMID: 12410312, DOI: 10.1038/nature01124.
- Mouse numb is an essential gene involved in cortical neurogenesisZhong W, Jiang M, Schonemann M, Meneses J, Pedersen R, Jan L, Jan Y. Mouse numb is an essential gene involved in cortical neurogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 6844-6849. PMID: 10841580, PMCID: PMC18761, DOI: 10.1073/pnas.97.12.6844.
- DLX‐1, DLX‐2, and DLX‐5 expression define distinct stages of basal forebrain differentiationEisenstat D, Liu J, Mione M, Zhong W, Yu G, Anderson S, Ghattas I, Puelles L, Rubenstein J. DLX‐1, DLX‐2, and DLX‐5 expression define distinct stages of basal forebrain differentiation. The Journal Of Comparative Neurology 1999, 414: 217-237. PMID: 10516593, DOI: 10.1002/(sici)1096-9861(19991115)414:2<217::aid-cne6>3.0.co;2-i.
- Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesisZhong W, Jiang M, Weinmaster G, Jan L, Jan Y. Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Development 1997, 124: 1887-1897. PMID: 9169836, DOI: 10.1242/dev.124.10.1887.
- Asymmetric Localization of a Mammalian Numb Homolog during Mouse Cortical NeurogenesisZhong W, Feder J, Jiang M, Jan L, Jan Y. Asymmetric Localization of a Mammalian Numb Homolog during Mouse Cortical Neurogenesis. Neuron 1996, 17: 43-53. PMID: 8755477, DOI: 10.1016/s0896-6273(00)80279-2.
- Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression.Zhong W, Mirkovitch J, Darnell JE. Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression. Molecular And Cellular Biology 1994, 14: 7276-84. PMID: 7523862, PMCID: PMC359262, DOI: 10.1128/mcb.14.11.7276.
- The expression pattern of a Drosophila homolog to the mouse transcription factor HNF-4 suggests a determinative role in gut formation.Zhong W, Sladek FM, Darnell JE. The expression pattern of a Drosophila homolog to the mouse transcription factor HNF-4 suggests a determinative role in gut formation. The EMBO Journal 1993, 12: 537-44. PMID: 8440243, PMCID: PMC413236.
- Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3 alpha, HNF-3 beta, HNF-3 gamma, and HNF-4.Avraham KB, Prezioso VR, Chen WS, Lai E, Sladek FM, Zhong W, Darnell JE, Jenkins NA, Copeland NG. Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3 alpha, HNF-3 beta, HNF-3 gamma, and HNF-4. Genomics 1992, 13: 264-8. PMID: 1612587, DOI: 10.1016/0888-7543(92)90241-j.
- Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily.Sladek FM, Zhong WM, Lai E, Darnell JE. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes & Development 1990, 4: 2353-65. PMID: 2279702, DOI: 10.1101/gad.4.12b.2353.