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代謝生理化学セミナー "Dlx gene regulation"のご案内

この度、ホメオボックス遺伝子Dlx群の研究でご高名なMarc EKKER博士をお招き

日時: 2007年7月10日(火) 17:00-18:00
会場: 東京大学医学図書館333号室
講師: Marc EKKER
Center for Advanced Research in Environmental Genomics&s_comma;
Department of Biology&s_comma; University of Ottawa&s_comma; Canada
Dlx gene regulation: a model for the evolution of expression control
mechanisms in duplicated genes.

The Dlx homeobox genes play an important role in the differentiation and
migration of neurons that will populate various regions of the
telencephalon. Vertebrate Dlx genes are generally organized as three
bigene clusters&s_comma; Dlx1/2&s_comma; Dlx3/4&s_comma; Dlx5/6&s_comma; with a short (~ 3-15 kb)
intergenic region. Genes of the vertebrate Dlx1/Dlx2 and Dlx5/Dlx6
bigene clusters are sequentially expressed in the forebrain and
branchial arches and show partially overlapping patterns of expression
that are well conserved in distant species&s_comma; suggesting concerted
mechanisms controlling their expression. We have identified four
cis-acting regulatory elements (CRE) with enhancer activity in the
Dlx1/2 and the Dlx5/6 intergenic regions as well as upstream of Dlx1.
The four CREs&s_comma; named URE2&s_comma; I12b&s_comma; I56i and I56ii&s_comma; are highly conserved&s_comma;
structurally and functionally&s_comma; between distant vertebrates. Although
they strongly overlap in their spectra of activity in the forebrain&s_comma; the
four enhancers diverge markedly in sequence. Detailed analyses of
forebrain enhancer activities in the mouse forebrain indicate that the
URE2 and I12b/I56i enhancers are active in distinct populations of
progenitor cells that will be give rise to different subtypes of
GABAergic interneurons in adult animals. For example&s_comma; the I12b and I56i
enhancers are active in most somatostatin interneurons whereas the URE2
enhancer is active in only a small percentage of somatostatin cells.
Using DNaseI footprinting and electrophoretic mobility shift assays&s_comma; we
characterized specific sites on the enhancers potentially bound by
transcription factors. Of these&s_comma; one sequence on I12b constitutes a
potential binding site for the MASH1 protein&s_comma; a finding that was
supported by chromatin immunoprecipitation assays. This provides
molecular evidence for a direct regulation of Dlx1/Dlx2 by MASH1.
Mutagenesis of individual binding sites on the CREs differentially
affected overall enhancer activity when tested in transgenic mice. This
mutational analysis revealed a crucial role for the DLX proteins in the
maintenance of their own expression. Our studies of CREs at the Dlx
loci suggest the existence of distinct genetic cascades involving Dlx
genes in specific subsets of cells in the telencephalon. Furthermore&s_comma;
we propose that the mechanisms responsible for the concerted expression
of Dlx genes during development appeared early following the duplication
event(s) that led to the existence of multiple Dlx bigene clusters in
vertebrates and remained largely conserved ever since.

栗原 裕基

東京大学大学院 医学系研究科
分子細胞生物学専攻 代謝生理化学分野
〒113-0033 東京都文京区本郷7-3-1
Tel. 03-5841-3496 Fax. 03-5684-4958