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First published online 5 November 2003
doi: 10.1242/dev.00846
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1 Center for Animal Resources and Development (CARD), Graduate School of Medical
and Pharmaceutical Sciences, Kumamoto University, Honjo 2-2-1, Kumamoto
860-0811, Japan
2 Molecular Genetics Laboratory, Division of Head and Neck Surgery, UCLA School
of Medicine, Los Angeles, CA 90095-7795, USA
3 Department of Cell and Molecular Biology, Tulane University, New Orleans, LA
70118, USA
4 Department of Genome Sciences, Graduate School of Medicine, Kobe University,
Kobe, Japan
5 Molecular Developmental Biology Group, Laboratory of Reproductive and
Developmental Toxicology, National Institute of Environmental Health Sciences,
NC 27709, USA
6 Mammalian Neurogenetics Group, Center for Childhood Communication, The
Children's Hospital of Philadelphia, PA 19104, USA
* Author for correspondence (e-mail: gen{at}kaiju.medic.kumamoto-u.ac.jp)
Accepted 29 August 2003
Extra-corporal fertilization depends on the formation of copulatory organs: the external genitalia. Coordinated growth and differentiation of the genital tubercle (GT), an embryonic anlage of external genitalia, generates a proximodistally elongated structure suitable for copulation, erection, uresis and ejaculation. Despite recent progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes of external genitalia formation.
Bone morphogenetic protein genes (Bmp genes) and their antagonists were spatiotemporally expressed during GT development. Exogenously applied BMP increased apoptosis of GT and inhibited its outgrowth. It has been shown that the distal urethral epithelium (DUE), distal epithelia marked by the Fgf8 expression, may control the initial GT outgrowth. Exogenously applied BMP4 downregulated the expression of Fgf8 and Wnt5a, concomitant with increased apoptosis and decreased cell proliferation of the GT mesenchyme. Furthermore, noggin mutants and Bmpr1a conditional mutant mice displayed hypoplasia and hyperplasia of the external genitalia respectively. noggin mutant mice exhibited downregulation of Wnt5a and Fgf8 expression with decreased cell proliferation. Consistent with such findings, Wnt5a mutant mice displayed GT agenesis with decreased cell proliferation. By contrast, Bmpr1a mutant mice displayed decreased apoptosis and augmented Fgf8 expression in the DUE associated with GT hyperplasia. These results suggest that some of the Bmp genes could negatively affect proximodistally oriented outgrowth of GT with regulatory functions on cell proliferation and apoptosis.
The DUE region can be marked only until 14.0 dpc (days post coitum) in mouse development, while GT outgrowth continues thereafter. Possible signaling crosstalk among the whole distal GT regions were also investigated.
Key words: External genitalia, Genital tubercle, BMP, FGF8, Noggin, WNT5A, Apoptosis, Cell proliferation, Distal urethral epithelium
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