Suppression of Insulin-Like3 Receptor Reveals the Role of β-Catenin and Notch Signaling in Gubernaculum Development

Kaftanovskaya, Elena M.; Feng, Shi Ting; Huang, Zaohua; Tan, Yiran; Barbara, Agustin M.; Kaur, Simrit; Truong, Anne; Gorlov, Ivan P.; Agoulnik, Alexander I.

doi:10.1210/me.2010-0330

Cited by 61 publications

(57 citation statements)

References 38 publications

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“…At 10 days after birth the process of testicular descent in mice is fully completed [24,25]. The testes are located in the scrotum and the gonocytes are differentiated into spermatogonial cells including a primary pool of SSCs.…”

Section: Resultsmentioning

confidence: 99%

The Fate of Spermatogonial Stem Cells in the Cryptorchid Testes of RXFP2 Deficient Mice

2013

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The environmental niche of the spermatogonial stem cell pool is critical to ensure the continued generation of the germ cell population. To study the consequences of an aberrant testicular environment in cryptorchidism we used a mouse model with a deletion of Rxfp2 gene resulting in a high intra-abdominal testicular position. Mutant males were infertile with the gross morphology of the cryptorchid testis progressively deteriorating with age. Few spermatogonia were identifiable in 12 month old cryptorchid testes. Gene expression analysis showed no difference between mutant and control testes at postnatal day 10. In three month old males a decrease in expression of spermatogonial stem cell (SSC) markers Id4, Nanos2, and Ret was shown. The direct counting of ID4+ cells supported a significant decrease of SSCs. In contrast, the expression of Plzf, a marker for undifferentiated and differentiating spermatogonia was not reduced, and the number of PLZF+ cells in the cryptorchid testis was higher in three month old testes, but equal to control in six month old mutants. The PLZF+ cells did not show a higher rate of apoptosis in cryptorchid testis. The expression of the Sertoli cell FGF2 gene required for SSC maintenance was significantly reduced in mutant testis. Based on these findings we propose that the deregulation of somatic and germ cell genes in the cryptorchid testis, directs the SSCs towards the differentiation pathway. This leads to a depletion of the SSC pool and an increase in the number of PLZF+ spermatogonial cells, which too, eventually decreases with the exhaustion of the stem cell pool. Such a dynamic suggests that an early correction of cryptorchidism is critical for the retention of the SSC pool.

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Section: Resultsmentioning

confidence: 99%

The Fate of Spermatogonial Stem Cells in the Cryptorchid Testes of RXFP2 Deficient Mice

2013

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“…In animal models of UDT, including deleted Ar, Wt1, Insl3, Rxfp2, Ctnnb, and Notch1 transgenic mice, fetal cremaster muscle development is absent, impaired, or disorganized. 6,7,10,14 The cremaster is more prominent in rodents, but imaging studies show embedded cremaster muscle bundles within human fetal gubernaculum. 4 Hutson and colleagues have focused primarily on the properties of the GCC that promote its elongation once inversion is complete.…”

Section: Discussionmentioning

confidence: 99%

“…Both hormones are required for enlargement and patterning of the cremaster muscle. 6,7 Transgenic inactivation of Rxfp2 leads to complete disorganization, lack of swelling and absent muscle development, in contrast to Ar inactivation targeting mesenchymal cells, which results in more subtle muscle defects. Similarly, Rxfp2 expression in the GCC is diffuse at E14, 8 but the RXFP2 protein becomes localized to the muscle layer by E20.5.…”

Section: Introductionmentioning

confidence: 99%

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Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes

et al. 2016

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Purpose Gubernaculum-cremaster complex (GCC) development is hormonally-regulated and abnormal in a cryptorchid rat model. Using cell tracking techniques and imaging, we studied myogenic phenotypes and fates in the fetal rat GCC. Materials and methods E17 (embryonic day 17) GCCs were labeled with CellTracker™ or DNA synthesis marker 5-ethynyl-2′-deoxyuridine (EdU), or immobilized in Matrigel™ and grown in culture. E17-21 GCC sections and cells were imaged using widefield and deconvolution immunofluorescence microscopy and muscle- and/or myofibroblast-specific antibodies. Deconvolved image stacks were used to create a 3-dimensional (3D) model of E21 GCC muscle. Results Paired-box 7 (PAX7)+ and myogenin+ muscle precursors were visible in a desmin-rich “myogenic zone” between muscle layers that elongated and became thicker during development. GCC inner mesenchymal cells expressed desmin and alpha smooth muscle actin (αSMA) at lower levels than in the myogenic zone. After pulse-labeling with CellTracker™ or EdU, mesenchymal cells became incorporated into differentiated muscle. Conversely, mesenchymal cells migrated beyond Matrigel™-immobilized GCCs, expressed PAX7 and fused to form striated myotubes. Mesenchymal GCC cell lines proliferated >40 passages and exhibited contractile behavior, but did not form striated muscle. Our 3D GCC model showed 2 orthogonal ventral layers and an arcing inner layer of muscle. Conclusions Our data suggest that mesenchymal cells in the peripheral myogenic zone of the fetal GCC contribute to formation of a distinctively-patterned cremaster muscle. Non-myogenic, desmin- and αSMA-positive GCC mesenchymal cells proliferate and exhibit a myofibroblast-like phenotype in culture. Intrinsic mechanical properties of these divergent cell types may facilitate perinatal inversion of the GCC.

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“…Gene targeting experiments in mice confirm requirement for Rxfp2 and Ar and confirm a role for Wnt and Notch signaling in gubernacular development, and confirm myogenesis as a key target of hormone action. 21,22 …”

Section: Discussionmentioning

confidence: 99%

Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

et al. 2015

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Purpose Based on a genome-wide association study (GWAS) of testicular dysgenesis syndrome (TDS) reporting possible association with TGFBR3, we analyzed GWAS data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. Materials and Methods We excluded samples based on strict quality control criteria, leaving 844 cases and 2718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform. Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of Group 1 and 2 data and selective genotyping of independent cases (n=330) and controls (n=324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. Results We identified suggestive (p≤1×10−4) association of markers in/near TGFBR3 including rs9661103 (OR 1.40, 95% CI 1.20,1.64, p=2.71×10−5) and rs10782968 (OR 1.58, CI 1.26,1.98, p=9.36×10−5) in Groups 1 and 2, respectively. In subgroup analyses, we observed strongest association of rs17576372 (OR 1.42, CI 1.24,1.60; p=1.67×10−4) with proximal and rs11165059 (OR 1.32, CI 1.15,1.38; p=9.42×10−4) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior GWAS signal (rs12082710) was marginal (OR 1.13, CI 0.99,1.28, p=0.09 for Group 1) and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild type and cryptorchid rat fetal gubernaculum. Conclusions These data suggest complex or phenotype-specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.

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Suppression of Insulin-Like3 Receptor Reveals the Role of β-Catenin and Notch Signaling in Gubernaculum Development

Cited by 61 publications

References 38 publications

The Fate of Spermatogonial Stem Cells in the Cryptorchid Testes of RXFP2 Deficient Mice

The Fate of Spermatogonial Stem Cells in the Cryptorchid Testes of RXFP2 Deficient Mice

Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes

Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

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