(The) roles of PI3K-Akt signaling in retinal development

Abstract

Development of retinal tissue is a coordinated process of retinal progenitor cell (RPC) proliferation and neuronal differentiation. Intracellular signaling events that regulate the balance between RPC proliferation and neuronal differentiation, therefore, determine the size and composition of nervous tissues. The PI3K-Akt signaling pathway plays key roles in proliferation, differentiation and survival by cell context dependent manner. In my PhD. thesis, I have demonstrated that phosphoinosite 3-kinase (PI3K)-Akt signaling plays a pivotal role in proliferation, maintenance, and neuronal differentiation of RPCs. I found that RPCs lacking phosphatase tensin homologue ( Pten ) gene, not only undergo hyperproliferation, but also complete neurogenesis earlier than their normal developmental schedule, resulting in their premature depletion in the mature retina. I further discovered that premature differentiation and precocious depletion of Pten-deficient RPCs are partially driven by negative correlation between Akt and Notch signaling. Notch intracellular domain (NICD) fails to form transcription activator complex in Pten-deficient RPCs, and thereby unable to support RPC maintenance. I, next, inverstigated functions of mTOR in retinal development, which is a downstream target of Akt regulating proliferation, cell growth and metabolism. RPCs deficient with Tsc1 gene, a negative regulator of mTORC1, divide faster than normal cell cycle leading to earlier neuronal differentiation. The accelerated cell cycle progression of Tsc1 deficient RPCs is derived by regulated turnover of cyclin B1, which is essential for G2/M cell cycle transition. Morevoer, not only differentiation but also functional maturation of retinal neurons including axon targeting and spontaneous firing of ganglion cells, and synaptic development of retinal neurons are accelerated in Tsc1 cKO retina. Finally, I discovered non-cell autonomous functions of mTORC1 in astrocyte development and consequent retinal blood vessel formation. In contrast to the gliosis of activated astrocytes in Tsc1 cKO retina later than post-natal day 14 ( P14 ), differentiation of migrating astrocyte precursor cells in early postnatal period is delayed in Tsc1 cKO retina, accordingly resulting in retarded vascularization. I showed that the hypovascularization in Tsc1 cKO retina results from delayed differentiation of astrocytes coupled with slow onset of vascular endothelial growth factor ( VEGF ), a potent stimulator for angiogenesis. Together, I propose two divergent PI3K-Akt signaling pathways that mediate Notch and mTORC1. The PI3K-Akt inhibits Notch signaling to promote neuronal differentiation of post-mitotic RPC daughter cells, whereas it activates mTORC1 for accelerating cell cycle progression of RPCs and consequent neuronal differentiation. Finally, I revealed non-cell autonomous functions of mTORC1 in astrocyte development and blood vessel formation. Collectively, my work provides evidences that PI3K-Akt signaling pathway plays key roles in retinal development by coordinating neuronal differentiation and functional maturation.