A Dual Role of Activin-like kinase 5 (ALK5)-mediated TGF Beta Signaling in Adult Neurogenesis

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Project Summary New neurons are added in the adult mammalian brain by a process known as adult neurogenesis and adult neurogenesis is a key player in functional outcomes for learning and memory. One of the two known niches of adult neurogenesis is the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. It is known that TGF-β signaling is crucial for neurogenesis during development while its role in adult neurogenesis remains unclear. Due to the lethal phenotype in early neonatal mice of the global TGF-β knockout mice, the precise role of TGF-β signaling in adult neurogenesis has been challenging to study. Chronic delivery of TGF-β in vivo inhibits neurogenesis; however, inhibition of TGF-β signaling via knockout of the type I receptor (Alk5) in mature and immature neurons also leads to compromised adult neurogenesis. Additionally, pharmacological modulation of TGF-β signaling in previous studies affect multiple cells types including neurons and microglia which are known to have an indirect role in regulating adult neurogenesis. Therefore, to understand the precise autonomous requirement of TGF-β signaling in the process of adult neurogenesis during different stages such as proliferation, differentiation, maturation, and migration, adult neural stem cell specific and inducible gene modulation models are needed. To circumvent these challenges in the field, we have generated NSC- specific TGF-β receptor type I (Alk5) or type II (TβRII) inducible knockout (iKO) mice which allows us to more specifically investigate how this signaling pathway affects adult NSCs and downstream progeny. Preliminary data from our lab shows in vitro pharmacological inhibition of TGF-β signaling with SB-431542 increases the proliferation of adult neural stem cell (NSCs) while treatment with TGF-β inhibits the proliferation. This implicates TGF-β signaling in playing an inhibitory role in the proliferation of adult NSCs. Additionally, our preliminary in vivo data from NestincreER-Alk5 iKO mice suggests TGF-β signaling is important for the maturation and migration of NSCs in the SGZ. We, therefore, hypothesize a dual role of TGF-β signaling in the neurogenic cascade which inhibits the proliferation of NSCs while simultaneously supporting maturation and migration in immature and mature neurons. The goal of this current study is to determine the precise functions and mechanisms of TGF-β signaling in regulation of adult neurogenesis through different stages and identify distinct target genes in each process. Although previous studies provide evidence of TGF-β signaling influencing adult neurogenesis, there are conflicting results throughout the field as TGF-β signaling is known to act in a highly context-dependent manner. With the specificity of our in vivo mouse models, this proposal will provide novel insight on the cellular and mechanistic processes involved with adult neurogenesis.