Irina Grishina, Ph.D.

Department of Urology

Research Interests

Embryonic development of the mammalian cloaca and genital tubercle

Several human genetic syndromes, such as Currarino, VACTERL, Hand-Foot-Genital, and Townes-Brocks, manifest with persistent cloaca, imperforate anus and malformations of the external genitalia. In the mouse, as in humans, the cloaca is a transient embryonic cavity at the caudal end of the hindgut. During normal development, the cloaca is separated into the rectal and urethral compartments by the caudal lateral mesenchyme known as the urorectal septum. The ventral cloacal epithelium and mesenchyme contribute to the genital tubercle, the primordium of the penis in males and the clitoris in females.

We found that mice null for Bone morphogenetic protein 7 (Bmp7) develop persistent cloaca, rectourethral fistula, and malformations of the external genitalia in males and females. We are currently investigating the role of BMP7 signaling and Bmp7-positive cell lineages in septation of the cloaca and morphogenesis of the genital urethra and the perineum (Xinyu Wu, Ellen Shapiro, Irina Grishina).

Development and tumorigenesis of the prostate gland

The prostate is a male sex accessory gland. Prostate develops by branching morphogenesis from the epithelium and mesenchyme of the urogenital sinus, the enlarged portion of the male urethra beneath the bladder. Androgens and developmental signaling molecules, Sonic hedgehog (Shh) and Fibroblast growth factor 10 (Fgf10) have been shown to promote prostate growth, while Bone morphogenetic proteins (BMPs) inhibit branching of the prostate epithelium.

We have shown that Bmp7 is expressed in the prostate epithelium and the periurethral mesenchyme, and that loss of Bmp7 results in a twofold increase in prostate branching. We further explore the mechanisms by which the developmental signals may be interpreted in the urogenital epithelium to regulate branching morphogenesis. We have shown that activity of the Notch1 receptor is specifically localized to the forming prostate buds, and that BMP7 signaling from the mesenchyme inhibits prostate branching and limits the number of domains with high Notch1 activity (Grishina et al., 2005).

Our current studies are directed toward elucidating the role of the Notch pathway during normal development and in tumorigenesis in the mouse prostate. We use several Cre/loxP systems to conditionally activate and deactivate Notch signaling in the mouse prostate epithelium (i) during embryonic and/or postnatal development, (ii) in the context of benign prostate hyperplasia (BPH) and (iii) in prostate epithelial neoplasia (PIN), a precancerous condition (Xinyu Wu, Kun Xu, Irina Grishina).

Publications

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