The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia

Numata

Proc. Natl. Acad. Sci. U.S.A.

et al. 2014

Self Cite

Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor (Ar) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.Mafb | masculinization | urethra | hypospadias | androgen receptor

Section: Discussionmentioning

confidence: 99%

“…However, such genes have not been identified. Recently, growth factor signals have been suggested to regulate the masculinization of the size of GTs (3,7). However, the modulation of such growth factor signals does not induce the urethral masculinization (3, 7).…”

mentioning

confidence: 99%

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Numata

Proc. Natl. Acad. Sci. U.S.A.

et al. 2014

Self Cite

“…There is literature stating that genotypes that have sonic hedgehog signalling (SHH) problems are likely to present with severe hypospadias and this genotype is also associated with defect on tissue repair and regeneration. [10][11] Our study has the limitation of being a non-concurrent cohort, although no randomization was applied; however, we are able to include all well-defined patients in the set timeframe. Furthermore, the baseline characteristics between groups in this study did not show any statistical significant difference, which supports no involvement of selection bias.…”

Section: Discussionmentioning

confidence: 99%

Single penile incision for combined hypospadias and inguinal surgery: A comparative study

Chua

Alqarni

Ming

et al. 2017

CUAJ

Introduction: We sought to compare the surgical outcomes of hypospadias repair with correction of inguinal pathology using a single penile incision vs. conventional approach using two incisions. Methods: This is a retrospective study that reviewed all patients who underwent concurrent surgical repair for both hypospadias and inguinal pathologies between January 2003 and November 2015. Patients were classified into Group A, conventional (inguinal or scrotal and penile incision) approach; or Group B, single penile incision approach. Baseline characteristics, including age, degree of hypospadias, type and laterality of inguinal pathology, operative time, and surgical outcomes, were collected. Between groups, variable comparisons were analyzed using Mann-Whitney U-Test and Fisher-exact test. Statistical significant set at <0.05. Results: Seventy-six patients (Group A: 40; Group B: 36) were eligible for study. Baseline characteristics of both groups were comparable, with no significant statistical difference. Overall mean operative time for Group A was 139.3 ± 56.2 minutes, while Group B was 107.8 ± 46.7 minutes (Z=2.6; U=470.5; p=0.009). Two patients in Group A and two patients in Group B had testicular ascension, all of which also had hypospadias-related complications (p=1.0). Hypospadias-related complications in Group A included seven urethrocutaneous fistulae and two repair dehiscence. Eight urethrocutaneous fistulae, one urethral stricture, and two repair dehiscence occurred in Group B (p=0.448). Surgical outcome appearance in both groups were comparable, with no statistically significant difference (p=0.466). Conclusions: Single penile incision for both hypospadias repair and correction of inguinal pathology is a feasible technique and comparable to the conventional approach, with similar surgical outcomes and shorter overall operative time.

Journal of Molecular Endocrinology

“…Miyagawa et al (2011) have shown that Shh is expressed in the urethral plate epithelium of mice during embryogenesis and that its signal is mediated through Gli2 in the mesenchyme. Gli2 mutants had hypoplasia of the genital tubercle and a cleft at the proximal ventral midline without androgen deficiency.…”

Section: Human Mutationsmentioning

confidence: 99%

Role of GLI2 in hypopituitarism phenotype

Arnhold¹,

França²,

Carvalho³

et al. 2015

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was R0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.