Directed neuronal navigation, including both cell body migration and growth cone path-finding, is a pre- requisite for the establishment of the precisely wired neural network and is essential for the proper function of the brain. Accumulating evidence suggests that growth cone navigation and neuronal cell navigation during early development share many similar features, including responses to a similar set of guidance cues, activation of specific intracellular signaling cascades and cytoskeletal changes for directed movements. For example, netrin-1, an evolutionally conserved long-range growth cone guidance cue essential for neural circuit formation during development, also directs cell migration of cortical neurons and olfactory neurons. Ca2+ signaling has emerged as a central player in mediating growth cone and cellular responses to many guidance cues, including netrin-1. The spatial and temporal regulation of Ca2+ signaling underlying directed neuronal navigation, however, is not well understood. While neural network formation occurs predominantly during the prenatal and early postnatal periods, new neurons are continuously generated from neural progenitors and integrated into the existing neural network in discrete regions of adult mammalian brain, including the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampus. Neurodevelopment in the adult brain recapitulates the major neural developmental milestones, from proliferation and fate specification of neural progenitors, to neuronal morphogenesis, cell migration, axon and dendritic guidance, and synapse formation by neuronal progeny. Because adult neurogenesis occurs in a significantly different environment from embryonic neurogenesis, whether the molecular mechanisms underlying neural development are conserved is not clear. Our long-term goal is to understand the molecular and cellular mechanisms that determine the motility and directionality of developing neurons in response to guidance cues and to develop therapeutic strategies to promote regeneration after injury or diseases of the human central nervous system (CNS). In the current project, we aim to understand the role of Ca2+ signaling in regulating neuronal navigation during early neural development and in the adult brain with the central hypothesis that TRPC, STIM1 and Orai proteins co-operate to set the basal and induced Ca2+ levels for directed motility of growth cones and neurons, using a combination of in vitro growth cone turning assay, immunocytochemistry, multi-photon confocal microscopy and electrophysiology. Our study will provide important information on the molecular mechanisms underlying neuronal navigation and may lead to novel insights as to whether neuronal navigation processes are similarly or differentially regulated in the mature brain, which is important for developing strategies in promoting regeneration.
The project aims at understanding the functional roles of STIM1, TRPC and Orai proteins in regulating the calcium changes for directed growth cone guidance and neuronal cell migration during embryonic development and in the adult brain. Findings from these studies may lead to novel strategies to functionally replace damaged or lost neurons and to promote endogenous repair after injury or degenerative neurological disease.
|Qian, Xuyu; Nguyen, Ha Nam; Song, Mingxi M et al. (2016) Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell 165:1238-54|
|Tang, Hengli; Hammack, Christy; Ogden, Sarah C et al. (2016) Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell 18:587-90|
|Gebara, Elias; Bonaguidi, Michael Anthony; Beckervordersandforth, Ruth et al. (2016) Heterogeneity of Radial Glia-Like Cells in the Adult Hippocampus. Stem Cells 34:997-1010|
|Zeng, Yaxue; Yao, Bing; Shin, Jaehoon et al. (2016) Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression. Mol Cell 61:153-60|
|Murai, Kiyohito; Sun, Guoqiang; Ye, Peng et al. (2016) The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat Commun 7:10965|
|Bonaguidi, Michael A; Stadel, Ryan P; Berg, Daniel A et al. (2016) Diversity of Neural Precursors in the Adult Mammalian Brain. Cold Spring Harb Perspect Biol 8:a018838|
|Zhang, Hongsheng; Kang, Eunchai; Wang, Yaqing et al. (2016) Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. Nat Commun 7:|
|Ming, Guo-li (2015) Neuroepigenetics: Introduction to the special issue on epigenetics in neurodevelopment and neurological diseases. Exp Neurol 268:1-2|
|Shin, Jaehoon; Ming, Guo-li; Song, Hongjun (2015) Seeking a roadmap toward neuroepigenetics. Neuron 86:12-5|
|Sun, Gerald J; Zhou, Yi; Stadel, Ryan P et al. (2015) Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain. Proc Natl Acad Sci U S A 112:9484-9|
Showing the most recent 10 out of 68 publications