RESEARCH

I. Complex Signaling Network for Border Formation in Neuroepithelium

Compartmentalization of three major optic neural tissues, neural retina (NR), retinal pigment epithelium (RPE), and optic stalk (OS), from unspecified neuroepithelium is mediated by distinctively expressed transcription factors in each tissue. These include Pax6&Rx in NR, Otx2&Mitf in RPE, and Vax&Pax2 in OS. The localized expressions of these fate determining transcription factors are regulated by external factors, including Shh, BMP, Wnt, and Fgf, which present in graded manner in the embryo (Kim et al. (2005); Kim and Lemke (2006)). We are studying the roles of intracellular signaling pathways, by which these external signals induce the expression of key intrinsic fate determinants for proper development of each compartment (Moon et al. (2018)).

II. Intracellular Signaling Pathways Regulating Neuronal Differentiation

The vertebrate retina is organized into well-ordered layers of cells that include six types of neurons and Müller glia. The generation of these cells occurs in a well-defined developmental schedule. The mechanisms underlying the retinal differentiation have been studied for several decades, and identified transcription factors that drive the differentiation of each retinal neuron subset in a combinatorial fashion. Thus, the fate of an uncommitted neural progenitor cell (NPC) is dependent on the specific array of transcription factors that are present when they exit from cell cycle to differentiate (Kim et al. (2017)). We are interested in the intracellular signaling hubs, which merge multiple external developmental signals and coordinately control to fate determining transcription factor activities. One of our current research interests is on the roles of PI3K-Akt-mTOR pathway as an intracellular signaling hub for temporally-specified retinal development and function (Jo et al. (2012); Choi et al. (2018))

III. RPE Homeostasis and Retinal Degenerative Diseases

Vision requires not only light perception by photoreceptors (PRs) followed by integration and transmission of signal to retinal neurons, but also needs specialized functions carried out by the highly polarized cells of the retinal pigment epithelium (RPE). Although the loss of RPE structural and functional integrity leads to many retinal degenerative diseases, little is known about the mechanisms that regulate functional and structural homeostasis of RPE. We have identified the roles of PI3K-Akt signaling pathway in impairment of structural homeostasis of RPE (Kim et al. (2008); Kang et al. (2009); Lee et al (2011)). We are further exploring the roles of downstream targets of Akt in RPE pathogenesis of retinal degenerative diseases.

IV. Non-cell autonomous Regulation of Neural Development by Homeodomain Transcription Factors

Past studies have revealed that homeodomain transcription factors (HM-TFs) play essential roles in the determination of cell fate in development. The studies have also revealed unexpected functions of HM-TFs, which do not simply remain in the nucleus as transcription regulators but also played as non-autonomously in neighboring cells through intercellular transfer (Kim et al. (2014); Kim et al. (2015); Lee et al. (2019)). We explore the new modes of intercellular communication mediated by HM-TF transfer for the development and maintenance of nervous tissues.

V. Guided Neuro-regeneration in Adult Tissues

Based on our discoveries on intercellular transfer of HM-TFs, we developed tools, by which we can resume neuronal development in adult. It includes the introduction of therapeutic HM-TFs into the nervous tissues or blocking the transfer of HM-TFs in the tissues for promoting the regeneration of specific neuronal lineages. The efforts will provide a new vision to cure the neurodegenerative diseases.

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