Investigating the role of apoptosis-stimulating of p53 protein 2 (ASPP2) in development of the central nervous system

Yin, J

Thesis

Investigating the role of apoptosis-stimulating of p53 protein 2 (ASPP2) in development of the central nervous system

Abstract:: Development of the structurally complicated central nervous system (CNS) involves a set of highly organized events including neurogenesis and neuronal migration. ASPP2 has been reported to be important for CNS development in both humans and mice. ASPP2 plays an important role in inhibiting excessive proliferation of neural stem cells (NSCs) and maintaining the polarity of the neuroepithelium in the developing mouse brain. However, the function of ASPP2 in neuronal migration and potential brain malformations caused by ASPP2 deficiency at postnatal stages remain uncharacterized.

This study found that Aspp2-KO mice show diminished olfactory bulbs, whose development relies on chain migration of neuroblasts in the rostral migratory stream (RMS). Subsequent in vivo and in vitro migration assays demonstrated that ASPP2 deficiency resulted in the impaired formation of the chain-like structure and neuroblasts migrating in the RMS. ASPP2 deficiency also impaired radial neuronal migration in the neocortex leading to periventricular nodular heterotopia (PNH), which was characterized by periventricular clusters of neurons that failed to migrate into the neocortex.

Dynamic regulation of the actin cytoskeleton, mediated by Rho GTPases and their downstream kinases, plays an essential role in developmental neuron migration disorders. A phosphoproteomic analysis using wild-type and ASPP2-KO U2OS cells indicates that ASPP2 may regulate the cytoskeleton through Rho-ROCK signalling. Indeed, my study demonstrated that ASPP2 physically interacted with ROCK2 and potentiated its phosphokinase activity towards MYPT1 and MLC2, thus positively regulating RhoA-mediated actomyosin stress fibre formation and cell migration. This work revealed novel functions of ASPP2 in regulating Rho-ROCK signalling, actin cytoskeleton, and neuronal migration.

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APA Style

Yin, J. (2020). Investigating the role of apoptosis-stimulating of p53 protein 2 (ASPP2) in development of the central nervous system [PhD thesis]. University of Oxford.

MLA Style

Yin, J. Investigating the Role of Apoptosis-Stimulating of p53 Protein 2 (ASPP2) in Development of the Central Nervous System. University of Oxford, 2020.

Chicago Style

Yin, J. 2020. “Investigating the Role of Apoptosis-Stimulating of p53 Protein 2 (ASPP2) in Development of the Central Nervous System.” PhD thesis, University of Oxford.
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