Computer‐based detection of neonatal changes to branching morphogenesis reveals different mechanisms of and predicts prostate enlargement in mice haplo‐insufficient for bone morphogenetic protein 4

Abstract

Early changes to branching morphogenesis of the prostate are believed to lead to enlargement of the gland in adult life. However, it has not been possible to demonstrate directly that alterations to branching during the developmental period have a permanent effect on adult prostate size. In order to examine branching morphogenesis in a quantitative manner in neonatal mice, a combination of imaging and computational technology was used to detect and quantify branching using bone morphogenetic protein 4 haplo-insufficient mice that develop enlarged prostate glands in adulthood. Accurate estimates were made of six parameters of branching, including prostate ductal length and volume and number of main ducts, branches, branch points, and tips. The results show that the prostate is significantly larger on day 3, well before the emergence of the phenotype in older animals. The ventral prostate is enlarged because the number of main epithelial ducts is increased; enlargement of the anterior prostate in mutant animals occurs because there are more branches. These lobe-specific mechanisms underlying prostate enlargement indicate the complex nature of gland pathology in mice, rather than a simple increase in weight or volume. This method provides a powerful means to investigate the aetiology of prostate disease in animal models prior to emergence of a phenotype in later life.

251: Transcriptomes of Human Prostate Cells

“…Recent work in a mouse model system has shown that BMP4 heterozygous adult animals have enlarged prostates due to increased branching of the prostate ducts during neonatal development [25]. BMP4 has also been shown to inhibit growth of the prostate cancer cell line LNCaP [26] and induce the expression of ID1, ID2, and ID3 in cell lines [23].…”

Retinoic acid induces prostatic bud formation

“…BMP4 inhibits budding in UGS organ culture and this effect can be overcome by the BMP antagonist NOGGIN (Cook et al, 2007;Lamm et al, 2001). Detailed analysis of the Bmp4 null heterozygote showed that functional haploinsufficiency for Bmp4 was associated with increased prostatic budding (Almahbobi et al, 2005) and increased indices of branching morphogenesis (Lamm et al, 2001). Our results show that, in the presence of DHT, SHH and the BMP4 antagonist NOGGIN induce supernumerary budding in the cultured UGS.…”

“…7). Hh signaling has been identified as a positive regulator of normal budding (Doles et al, 2006;Lamm et al, 2002;Podlasek et al, 1999) while BMP4 has been shown to be an inhibitor of prostatic budding (Almahbobi et al, 2005;Lamm et al, 2001). Thus, the RA-induced increase in prostatic bud formation may be mediated by reciprocal changes in expression of Shh and Bmp4.…”

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

“…The postnatal development of the AROMϩ prostate was examined the computational analysis of branching morphogenesis, as previously described. 20 This analysis revealed that the postnatal development of the AROMϩ prostate was completely normal.…”

“…20 Briefly, VP or AP were dissected from the urogenital tracts of neonatal day 0 and day 3 wildtype and AROMϩ mice and prepared for wholemount immunostaining of epithelial cell cytokeratins. Six parameters of branching were recorded and analyzed; specifically, prostate ductal length, volume, number of main ducts, branches, branch points, and tips.…”