Cell Death Serves as a Single Etiological Cause of a Wide Spectrum of Congenital Urinary Tract Defects

Abstract

Purpose We genetically disrupted the Wolffian duct (WD) in mice to study the affected organogenesis processes and to test the hypothesis that cell loss can be the developmental basis for a wide spectrum of congenital anomalies in the kidney and urinary tract. Materials and Methods We use Hoxb7-Cre transgenic lines (HC1 and HC2) to induce diphtheria toxin (DT) production from a ROSADTA allele, disrupting the wolffian duct and derivatives. Results The first set of mutants (HC1;ROSADTA/+) exhibited agenesis of the kidney, ureter, and reproductive tracts. The second set of mutants (HC2;ROSADTA/+) exhibited diverse defects, including renal agenesis/hypoplasia, hydronephrosis, hydroureter, ureter-vas deferens fistulas in males and ureter-oviduct/uterus fistulas in females. The phenotypic differences correspond to the degree of apoptosisinduced caudal truncation of the wolffian duct, which is less severe and more variable in HC2;ROSADTA/+ mice. Whenever the wolffian duct failed to reach the urogenital sinus, the ureter failed to separate from the wolffian duct, suggesting that ureteral migration along the common nephric duct to the cloaca and the subsequent common nephric duct degeneration constitute the only pathway for separating the ureter and WD derivatives. Conclusions The diverse and severe defects observed emphasize the central role of the wolffian duct in providing progenitors and signals for urogenital development. These results also indicate that the quantitative difference in cell deathinduced caudal truncation of the wolffian duct can lead to a wide range of qualitatively distinct defects, and that cell death can serve as a single etiological cause of a wide spectrum of congenital kidney and urinary tract defects.

Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms

“…Since most mutants died from tumor burden and other comorbidities associated with NFATc1 activation in other tissues, it is currently unknown if any of the NFATc1-induced tumors will become metastatic if given sufficient time to progress in these mice. Although epididymal tumors were not extensively characterized in this study, Hoxb7-Cre expression in the epididymal epithelia, a Wolffian duct derivative, is well established (11, 12), making these tumors most likely primary tumors induced by NFATc1 activation but not metastasis from other sites. Besides the three sites mentioned, tumors have not been found in other places with known Hoxb7-Cre expression, including neuronal tissues, renal collecting duct, and ureteral epithelia.…”

“…To study the role of NFAT signaling in urogenital organs, we created a transgenic model for inducible NFATc1 activation in cells targeted by the Hoxb7-Cre transgene (11, 12) that has known expression in the Wolffian duct, an embryonic structure providing progenitors for multiple urogenital organs (Fig. 1).…”

An illustrated anatomical ontology of the developing mouse lower urogenital tract

“…Both seminal vesicles and ductus deferens are connected to the UGS ridge via the ND-derived ejaculatory ducts, and disrupting ND development in males results in loss of these structures ( Fig. 4C,D; Guo et al, 2011). The male UGS ridge becomes the verumontanum ( Fig.…”

Scrotal abscess: Varied etiology, associations, and management

“…This can also be due to defects of genes related to GDNF/RET pathway, like Spry1, Gata3, Bmp4, Slit2/Robo2, Foxc1/2, Pax2, Eya1/Six1, and Sall1. [ 10 ] Quantitative difference in the apoptosis of caudal Wolffian duct/common nephrogenic cord,[ 10 13 ] failure of reciprocal interaction between ureteric bud and metanephric blastemal,[ 10 ] obstructive ectopic ureter and cranial origin of ureter bud,[ 14 15 16 17 ] and proliferative mesenchymal abnormality around common mesonephric duct[ 8 ] can cause RA, persistent mesonephric duct, ectopic ureter, and ureter-genital fistula. [ 10 14 17 ] Severe mesenchymal abnormality may also result in ARM.…”

“…Ectopic ureter may terminate in to the supra sphincteric genitourinary tract, usually involving the seminal vesicle, vas, prostatic urethra and rarely presents as recurrent scrotal abscess due to urogenital reflux. [ 13 14 15 16 17 ] Persistent mesonephric duct, ectopic vas, ectopic ureter are common causes for recurrent unilateral epididymitis postpull thorough in the young infantile ARMs. [ 15 16 ] Magnetic resonance urography with gadolinium contrast enhancement is the investigation of choice as it gives anatomy and functioning aspect of the kidney and ureters.…”