Faculty Bibliography

PURPOSE OF REVIEW: This review focuses on recent advances in molecular embryology of the upper and lower urinary tract with an emphasis on clinical correlation in order to gain a better understanding for the mechanism of congenital anomalies. RECENT FINDINGS: Normal morphogenesis of the kidney, ureteral bud differentiation, ureteropelvic junction formation, and bladder and trigone development are regulated by complex epithelial-mesenchymal signaling events. Failure of these signaling events to occur at specified times results in developmental anomalies. Immunohistochemical staining using animal and human tissues provides insights into the timing of various signaling events during development. Murine knockout models examine the role of various signaling molecules in genitourinary organogenesis. Lineage studies map the fate of cells in developing genitourinary tissues. Some of the most important findings include the role of bone morphogenetic protein-4 in morphogenesis of the kidney, the importance of the mesenchyme associated with the proximal and distal segments of the ureter in directing differentiation, the role of bone morphogenetic protein-4 signaling in smooth muscle formation at the ureteropelvic junction, and the predominant contribution of bladder smooth muscle in forming the trigone. SUMMARY: Recent studies have begun to unravel the complex molecular and cellular mechanisms for many common congenital anomalies of the genitourinary tract. A more precise understanding of these developmental events may provide insights into normal and abnormal development

Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans

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