ABSTRACT
Signaling by Bone morphogenetic proteins (Bmps) has multiple and diverse roles in patterning and morphogenesis of the kidney, eye, limbs and the neural tube. Here, we employed the Bmp7(lacZ) strain to perform a detailed analysis of Bmp7 expression and the null phenotype during development of the mouse urogenital system. The urethral compartment originates in mid-embryogenesis from the ventral part of the cloaca, a transient cavity at the caudal end of the hindgut. At mid-gestation, Bmp7 expression was detected within several specific domains in the cloacal epithelium and mesenchyme. In late embryogenesis, Bmp7 expression was present in the urethra, rectum, the urethral glands, corpus cavernosum, and in the male and female genital ducts. Importantly, loss of Bmp7 resulted in arrest in cloacal septation, and severe defects in morphogenesis of the genital urethra and mesenchyme. Together, our analysis of Bmp7 expression and the null phenotype, indicates that Bmp7 may play an important role in re-organization of the epithelium during cloacal septation and morphogenesis of the genital tubercle.
Subject(s)
Bone Morphogenetic Protein 7/genetics , Gene Expression Regulation, Developmental , Urethra/metabolism , Urogenital System/metabolism , Animals , Bone Morphogenetic Protein 7/physiology , Cloaca/embryology , Cloaca/metabolism , Embryo, Mammalian/embryology , Embryo, Mammalian/metabolism , Epithelium/embryology , Epithelium/metabolism , Female , Gene Expression Profiling , Genotype , In Situ Hybridization , Male , Mesoderm/metabolism , Mice , Mice, Knockout , Phenotype , Time Factors , Urethra/embryology , Urogenital System/embryologyABSTRACT
The mouse prostate gland develops by branching morphogenesis from the urogenital epithelium and mesenchyme. Androgens and developmental factors, including FGF10 and SHH, promote prostate growth (Berman, D.M., Desai, N., Wang, X., Karhadkar, S.S., Reynon, M., Abate-Shen, C., Beachy, P.A., Shen, M.M., 2004. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev. Biol. 267, 387-398; Donjacour, A.A., Thomson, A.A., Cunha, G.R., 2003. FGF-10 plays an essential role in the growth of the fetal prostate. Dev. Biol. 261, 39-54), while BMP4 signaling from the mesenchyme has been shown to suppresses prostate branching (Lamm, M.L., Podlasek, C.A., Barnett, D.H., Lee, J., Clemens, J.Q., Hebner, C.M., Bushman, W., 2001. Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate. Dev. Biol. 232, 301-314). Here, we show that Bone Morphogenetic Protein 7 (BMP7) restricts branching of the prostate epithelium. BMP7 is expressed in the periurethral urogenital mesenchyme prior to formation of the prostate buds and, subsequently, in the prostate epithelium. We show that BMP7(lacZ/lacZ) null prostates show a two-fold increase in prostate branching, while recombinant BMP7 inhibits prostate morphogenesis in organ culture in a concentration-dependent manner. We further explore the mechanisms by which the developmental signals may be interpreted in the urogenital epithelium to regulate branching morphogenesis. We show that Notch1 activity is associated with the formation of the prostate buds, and that Notch1 signaling is derepressed in BMP7 null urogenital epithelium. Based on our studies, we propose a model that BMP7 inhibits branching morphogenesis in the prostate and limits the number of domains with high Notch1/Hes1 activity.
