Neurogenesis plays an important role in the pathogenesis of many neural diseases including neurodevelopmental defects, depression, epilepsy, stroke and neurodegenerative diseases. There is a fundamental gap in understanding how impairment of both embryonic and adult neurogenesis influences such diseases. NIBP is a novel regulator of the signaling for nuclear factor kappa B (NFkB) and implicated in neural developmental disorders such as mental retardation, autism, hearing loss, etc. There is an urgent need for understanding the underlying cause-effects and mechanisms of NIBP/NFkB signaling in neurodevelopmental disorders. The long-term goal is to understand how NIBP/NFkB signaling can be manipulated for preventive and therapeutic purposes. The objective of this particular proposal is to define the role and mechanisms of NIBP/NFkB signaling in embryonic and adult neurogenesis. The central hypothesis is that NFkB signaling, controlled by NIBP and other related proteins, induces a set of genes to shut down the stemness and trigger the differentiation, maintains the cellular survival and guides neuronal cell fate commitment during neurogenesis. The hypothesis has been formulated on the basis of previous studies and the applicants'own preliminary data showing that (1) NIBP/NFkB signaling plays key roles in modulating early neural differentiation;(2) Functional knockdown of NIBP in zebrafish leads to severe defects of brain development;(3) Conventional and conditional cre-mediated NIBP knockout in mice and cultured neural stem/progenitor cells (NSCs/NPCs) attenuates neuronal differentiation. The rationale for the proposed research is that identification of NIBP action at various stages of neurogenesis will contribute fundamental knowledge about the molecular and cellular bases of neurodevelopment in embryonic neural tissues and neural-maintenance in adult brains. This hypothesis will be tested by pursuing 3 specific aims.
In aim 1, the detailed roles of NIBP/NFkB signaling in mouse embryonic and adult neurogenesis will be delineated.
In aim 2, the role of NIBP/NFkB signaling in regulating neural induction and neuronal lineage differentiation in zebrafish embryos will be elucidated.
In aim 3, the molecular mechanisms for NIBP actions in neurogenesis will be explored by elucidating how NIBP regulates NFkB signaling in NSCs/NPCs and determining the extent by which activation or inhibition of NIBP/NFkB-dependent target genes influence NSC stemness and early differentiation in mouse NSCs/NPCs and zebrafish embryos. The proposed work is expected to obtain detailed functions of NIBP/NFkB signaling in early neurogenesis and neuronal lineage specificity, as well as specific genes to control and maintain early neural differentiation. The results are also able to provide broaden apprehensive views of the pathogenesis of neurodevelopmental disorders, neurodegenerative diseases, and pathological/physiological responses after neural injuries. Such results are expected to produce an important positive impact on the field of neurogenesis and shed light on therapeutics for neurodevelopmental disorders.
The proposed research is relevant to public health because the discovery of a novel function and regulatory mechanism of NIBP/NFkB signaling in early neurogenesis and neuronal lineage differentiation is ultimately expected to increase the understanding of the pathogenesis of mental disorders and neurodegenerative diseases. It also shed light on therapeutics for neural diseases. The project is relevant to NIH mission because the fundamental knowledge of neurogenesis and cell fate decision help to extend healthy life and reduce burdens of human disability.
|Zhang, Y; Bitner, D; Pontes Filho, A A et al. (2014) Expression and function of NIK- and IKK2-binding protein (NIBP) in mouse enteric nervous system. Neurogastroenterol Motil 26:77-97|