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J. Biol. Chem., Vol. 279, Issue 23, 24733-24744, June 4, 2004

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Notch1-expressing Cells Are Indispensable for Prostatic Branching Morphogenesis during Development and Re-growth Following Castration and Androgen Replacement^*

Xi-De Wang**, Jianyong Shou**, Peter Wong¶, Dorothy M. French¶, and Wei-Qiang Gao||

From the Departments of Molecular Oncology and ^¶Pathology, Genentech, Inc., South San Francisco, California 94080

Notch expression is frequently associated with progenitor cells, and its function is crucial for development. Our recent work showing that Notch1 is selectively expressed in basal epithelial cells of the prostate and higher Notch1 expression during development suggests that Notch1-expressing cells may define progenitor cells in the prostate. To test this hypothesis, we have generated a transgenic mouse line in which the Notch1-expressing cells can be ablated in a controlled manner. Specific targeting was achieved by expressing the bacterial nitroreductase, an enzyme that catalyzes its substrate into a cytotoxin capable of inducing apoptosis, under the Notch1 promoter. Cell death in transgenic prostate was confirmed by histological analyses including terminal dUTP nick-end labeling and caspase 3 immunocytochemical staining. We evaluated the consequences of ablation of Notch1-expressing cells in two systems, organ culture of early postnatal prostates and re-growth of prostate in castrated mice triggered by hormone replacement. Our data show that elimination of Notch1-expressing cells inhibited the branching morphogenesis, growth, and differentiation of early postnatal prostate in culture and impaired prostate re-growth triggered by hormone replacement in castrated mice. Furthermore, we found that Notch1 expression following castration and hormone replacement was concomitant with known basal cell markers p63 and cytokeratin 14 and was high in the proliferative human prostate epithelial cells. Taken together, these data suggest that Notch1-expressing cells define the progenitor cells in the prostatic epithelial cell lineage, which are indispensable for prostatic development and re-growth.

Received for publication, February 13, 2004 , and in revised form, March 15, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Both authors contributed equally to this work.

Present address: Integrative Biology, Lilly Research Laboratories, Indianapolis, IN 46285.

^|| To whom correspondence should be addressed: Dept. of Molecular Oncology, MS 72, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Tel.: 650-225-8101; Fax: 650-225-6240; E-mail: gao{at}gene.com.

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