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日時: 2007年10月9日(火) 16:30-18:00
会場: 東京大学大学院医学系研究科1号館1階講堂

講師 1.
山田 源 博士

"Coordinated organogenesis in embryos; orchestrated growth factor signaling
and EMT regulation for reproductive/urogenital organ formation and caudal

We have been working on the role of several growth factor cascades for
reproductive/urogenital organ formation. Coordinated organogenesis is one of
the key issues not only for such reproductive organs but a general problem
for several organogenesis. By analyzing one of the growth factor cascade&s_comma;
hedgehog pathway&s_comma; we found immature mesenchyme in the caudal embryos can
contribute to several different organs. We also recently found the
regulation EMT (Epithelial-Mesenchymal Transition) is crucial for caudal
embryogenesis. Our recent observations will be discussed.

講師 2.
Giovanni Levi博士
Evolution des Regulations Endocriniennes&s_comma; CNRS&s_comma; UMR5166&s_comma;
Museum National d’Histoire Naturelle&s_comma; Paris&s_comma; France

"Role of Dlx5 and Dlx6 genes in the control of limb and craniofacial

Dlx genes are homeobox-containing genes involved in the control of limbs and
head development. Inactivation of these genes by homologous recombination
leads to severe limb and craniofacial lesions. In the first part of the talk
the role and regulation of Dlx genes in the control of craniofacial
development will be discussed. In particular data supporting the notion of a
dosage effect of homeobox genes and their activating signals in the control
of head morphogenesis will be presented. The regulation of Dlx genes during
craniofacial development will then be addressed. In particular the effects
of Retinoic Acid (RA) on the activation of Dlx genes will be presented.
Intake of retinoic acid (RA) or of its precursor&s_comma; vitamin A&s_comma; during early
pregnancy is associated with increased incidence of craniofacial lesions.
The origin of these teratogenic effects remains enigmatic as in cranial
neural crest cells (CNCCs)&s_comma; which largely contribute to craniofacial
structures&s_comma; the RA-transduction pathway is not active. Recent results
suggest that RA could act on the endoderm of the first pharyngeal arch
(1stPA)&s_comma; through a RARs-dependent mechanism. We show that RA provokes
dramatically different craniofacial malformations when administered at
slightly different developmental times within a narrow temporal interval
corresponding to the colonization of the 1st PA by CNCCs. We provide
evidence showing that RA acts on the signalling epithelium of the 1st PA
gradually reducing the expression of endothelin-1 and Fgf8. These two
molecular signals are instrumental in activating Dlx genes in incoming CNCCs
thereby triggering the morphogenetic programs&s_comma; which specify different jaw
elements. New data will be presented on the role of CNCC on the patterning
and differentiation of head muscles. Similar experiments performed in
Xenopus show that treatments as short as one minute of the embryo with RA
during the period of 1st PA colonization by CNCC are sufficient to provoke
serious craniofacial defects in the larva. Our results might provide a
conceptual framework for the rise of jaw morphotypes characteristic of
In the second part of the seminar the interaction of Dlx5 and 6 with other
transcription factors essential for the control of limb development will be
discusses. The congenital malformation Split Hand-Foot (SHFM&s_comma; or
ectrodactyly) is characterized by a medial cleft of hands and feet&s_comma; and
missing central fingers. Five genetically distinct forms are known in human;
the most common (type-I) is linked to deletions of DSS1 and the
distalless-related homeogenes DLX5 and DLX6. As Dlx5;Dlx6 double knockout
mice show a SHFM-like phenotype&s_comma; the human orthologs are believed to be the
disease genes. SHFM-IV and Ectrodactlyly-Ectodermal dysplasia-Cleft lip
(EEC) are caused by mutations in p63&s_comma; an ectoderm-specific p53-related
transcription factor. These phenocopies may underlie the existence of a
regulatory cascade involving the disease genes. We show that p63 and Dlx
proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In
homozygous p63null and p63EEC mutant limbs the AER fails to stratify and
expression of four Dlx genes is strongly reduced; however in p63+/EEC limbs
only Dlx5-Dlx6 expression is reduced in spite of a normally stratified AER
and normal development. In vitro DNp63a activates transcription from the
Dlx5 and Dlx6 promoters&s_comma; an activity abolished by EEC and SHFM Type I
mutations. ChIP analysis shows that p63 is associated to the Dlx5 promoter.
Thus&s_comma; p63 and Dlx5;Dlx6 take part in a pathway relevant in the
aetio-pathogenesis of SHFM.


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