Notch Sigaling in Morphogenesis of Mouse Prostate

New York University School Of Medicine, New York NY

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Abstract

DESCRIPTION (provided by applicant): Our long-term objectives are to determine the basic mechanisms controlling branching morphogenesis and epithelial differentiation in prostate gland, i. e. to understand how growth control and cell differentiation are correlated during normal organogenesis, and what may be the weak links contributing to innate or acquired glandular pathologies, in particular benign and malignant prostate tumors. Towards this aim the goals of the present proposal are to explore the role of Notch signaling in normal prostate organogenesis: in prostate branching morphogenesis, in defining the epithelial prebud sites; and in cell fate choice, in epithelial differentiation, progenitor cell maintenance and proliferation. In the first specific aim, we will investigate the expression and activity of Notch pathway genes during embryonic and postnatal development of mouse prostate. In specific aims two, developmental regulation of Notch pathway by mesenchymal signaling factors will will be explored in vivo, in prostates from Bmp7 and Gli3 mutant mouse, and in organ culture. In specific aim four, we will assess the effect of gain of Notch function and inhibition of Notch function in epithelial proliferation, morphogenesis and differentiation vie retroviral infections, antisense oligonucleotide assays, and analysis of Hes knockout prostates. Results of this work will aid towards greater understanding of branching morphogenesis and differentiation of prostate and other glandular organs, such as mammary gland and lungs, and lead towards further insight on how benign and malignant epithelial tumors may arise and overcome the tissue specific growth restrictions. In perspective, those results may aid towards novel therapies to overcome genetic or injury inflicted pathologies in branched glands.