Poster presentation, P15
Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011
BRN2 phosphorylation regulates melanoblast migration and proliferation through PAX3 and MITF-M
| SPEAKER | I. Berlin #whois submiter ? |
| AUTHOR(s) | I. Berlin, L. Denat, A.-L. Steunou, I. Puig, D. Champeval, S. Colombo, K. Roberts, E. Bonvin, Y. Bourgeois, V. Delmas, I. Davidson, L. Nieto, C.R. Goding, L. Larue |
BRN2 is a POU domain transcription factor overproduced in human melanoma cell lines and involved in melanocyte proliferation and migration. The T361 and S362 residues of BRN2, located within the POU domain, are conserved throughout the POU proteins family. We investigated the importance of phosphorylation of these residues for migration and proliferation by mutation, replacing T361 and S362 in the wild-type form of BRN2 (BRN2TS) by two alanine residues (BRN2AA). BRN2TS was phosphorylated by PKA whereas BRN2AA was not. The T361 and S362 residues are the most important targets of this kinase. In vitro, BRN2TS overproduction induced proliferation and slightly repressed migration in murine melanocytes whereas BRN2AA overproduction repressed both proliferation and migration. We investigated the role of BRN2TS and BRN2AA in vivo, after generating transgenic mice overproducing either BRN2TS (Tyr::BRN2TS) or BRN2AA (Tyr::BRN2AA) specifically in the melanocyte lineage, using tyrosinase promoter. Tyr::BRN2TS mice showed a slight hyperpigmentation, whereas Tyr::BRN2AA mice had a white spot on the belly. These phenotypes were associated with changes in migration an dproliferation during establishment of the melanocyte lineage. Indeed, on day 13.5 of embryonic development (E13.5), Tyr::BRN2TS embryos had slightly more melanoblasts than wild-type embryos, which had more melanoblasts than Tyr::BRN2AA embryos strongly suggesting that T361 and S362 residues are involved in the proliferation of melanoblasts and melanocytes in vivo. BRN2 is known to regulate Pax3, Gadd45 and NotchL positively and Mitf-M negatively. Moreover, Pax3 and Mitf-M are implicated in migration and proliferation of the melanocyte lineage. We thus investigated the regulation of Pax3 and Mitf-M by BRN2TS and BRN2AA at the molecular and genetic levels. Mitf-M transcription is repressed similarly by BRN2TS and BRN2AA whereas Pax3 transcription is induced by BRN2TS but repressed by BRN2AA. These results suggest that the regulation of proliferation and migration mediated by BRN2 involves Pax3 and Mitf-M and that BRN2 phosphorylation controls the regulation of proliferation mediated by Pax3.
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