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Professor KONDOH, Hisato, Ph.D. +81-6-6879-7964
Associate Prof. HIGASHI, Yujiro, Ph.D. +81-6-6879-7964
Associate Prof. KAMACHI, Yusuke, Ph.D. +81-6-6879-7964
Assistant Prof. UCHIKAWA, Masanori, Ph.D. +81-6-6879-7964

FAX +81-6-6877-1738
Postal Mail Address Graduate School of Frontier Biosciences, Osaka University
1-3 Yamadaoka, Suita, Osaka 565-0871, Japan

This group investigates regulation of the embryonic development, how intercellular signaling molecules act, how cells respond to the signals and activate transcriptional regulators, and how the action of transcriptional regulators cause cell differentiation. The major subject of the research is the differentiation of the primitive central nervous system and the sensory organs exemplified by eye lens.

1 Induction of the central nervous system and the sensory organ primordial from the ectoderm.

Induction signals from nearby tissues activates master transcriptional regulator genes, such as Sox2. Investigation of the regulation of such genes will reveal fundamental mechanisms of the induction of cell differentiation.
Fig. 1 An enhancer of the Sox2 gene responding to the neural induction signal is activated in the tissue area surrounding Hensen's node.

2 Molecular mechanisms of differentiation of lens cells and neural primordium.

Multiple transcriptional regulators interact in initiation and progression of cell differentiation process. Lens cells and neural primordium share SOX2 as the major transcriptional regulator. Interaction of SOX2 with other transcriptional regulators in differentiation of these tissues is investigated.
Fig. 2-1 Neural plate, the neural primordium, expresses Sox2.
Fig. 2-2 Lens differentiation initiates when Pax6 and Sox2 genes are expressed together in the head ectoderm.

3 Molecular interactions among SOX, Pax and POU transcriptional regulators in cell differentiation.

Not a single transcriptional regulator but molecular complexes of the regulators interact with various regulatory DNA sequences and determine cell states. Molecular mechanisms of the interaction and of the transcriptional regulation are investigated.
Fig. 3. Pax6 and SOX2 form a molecular complex and activate delta-crystallin enhancer.

4 Basic function of SOX family regulators in cell differentiation.

SOX proteins interact with various partner factors, and a combination of a SOX-partner pair selectively activates a specific set of genes and determines cell differentiation.
Fig. 4 Examples of SOX-partner combinations in cell differentiation.

5 Role of ZFHX1 family proteins in embryogenesis

The vertebrate ZFHX1 family consists of the two closely related proteins, SIP1 (Smad-interacting protein 1) and dEF1 (d-crystalline enhancer factor 1). The ZFHX1 proteins are the transcription factors, which are evolutionally conserved from fly to man, and harbor two zinc fingers clusters flanking a homeodomain-like sequence (HD) and one or more binding sites for the co-repressor CtBP. Both dEF1 and SIP1 bind CACCT consensus DNA sequence and act as transcriptional repressors. The recent studies indicate their involvement in the pathways of TGFb and Hedgehog signaling. To clarify the roles of these proteins in embryogenesis, knockout mice of these Zfhx1 family genes have been produced.
Fig. 5. ZFHX1 family proteins and the phenotype of the SIP1 Knockout mouse embryo: the somites are small and irregular, and the neural tube is not closed, supporting the view that SIP1 plays an important role in morphogenesis of these tissues.

6 Unorthodox pathways of cell differentiation.
There are unorthodox pathways of cell differentiation apparently disregarding cell lineages, which are collectively called "transdifferentiation", and is often adopted in tissue regeneration. Process of transdifferantiation and regeneration of lens is compared with embryonic lens differentiation to reveal the fundamental mechanisms of cell differentiation.

Fig. 6 Multiple pathways to give rise to lens cells.

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