Neural stem cells (NSCs) are the building blocks of the brain, lying at the core of brain development, circuit formation and repair. NSCs have the ability to produce more NSCs (self- renew) or give rise to neurons and glial cells (differentiation. Dysfunction in NSC self-renewal and differentiation can result in severe pathologies at various stages of life. The proposed work examines the impact of Akt and mTOR pathway activation on the proliferation and differentiation in postnatal neural stem cells (NSCs). Dysfunction in both Akt and mTOR regulation is known to contribute to the development of Tuberous Sclerosis and Autism Spectrum Disorder in the developing brain. Despite a wealth of studies on brain development, very little is known about the physiological function of Akt-mTOR on NSC fate decisions. Recent studies by the applicant have shown that activation of mTOR Complex 1 (mTORC1) can trigger NSCs to differentiate, increasing neuron production. The objective of the proposed project is to identify the independent physiological functions of Akt and mTOR in NSC proliferation and differentiation. It is hypothesized that Akt activation is necessary to prime NSC for proliferation; while mTOR activation biases NSCs to differentiate into neurons following cell cycle entry. It is also hypothesized that Akt acts through mTOR to increase neuron production, but acts independently to regulate dendritic growth and spine density. To test these hypotheses, a comparison will be made of cell fates, migratory patterns and morphology of the progeny produced by NSCs in three ways: 1) Postnatal electroporation of plasmids that disrupt the Akt and mTOR pathways in the subventricular zone (SVZ) of neonatal mice, 2) ex vivo analysis of transfected cells, and 3) morphological analysis of neurons produced in the olfactory bulb. This project will provide a foundation for further exploration of the downstream targets of Akt signaling as they relate to NSC physiology. The knowledge gained by this project will provide new insight into how Akt-mTOR signaling in NSCs can progress to pathological states observed in diseases like Tuberous Sclerosis and Autism Spectrum Disorder. The long-term goal is to advance understanding of the molecular mechanisms that influence the progression of neurodevelopmental disorders.
Tuberous Sclerosis (TS) and Autism Spectrum Disorders (ASD) are significant medical problems for millions of Americans. Many TS patients are co-morbid with ASD and present with impaired social interactions, repetitive behaviors, seizures and cognitive deficits. Currently, there are currently no effective pharmaceutical interventions fo either TS or ASD. A key question is whether problems at the neural stem cell level translate into these behavioral deficits. To address this question, our proposed research investigates the molecular mechanisms that control neural stem cell behavior in order to better understand the progression of TS and ASD.
| LiCausi, Francesca; Hartman, Nathaniel W (2018) Role of mTOR Complexes in Neurogenesis. Int J Mol Sci 19: |
