Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent?

Churchill, James; Buraundi, Silverton; Farmer, Pamela J.; Li, Ruili; Southwell, Bridget R.; Hutson, John M.; Balic, Adam

doi:10.1016/j.jpedsurg.2011.09.025

Cited by 18 publications

(8 citation statements)

References 15 publications

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“…Both these processes, maturation of the gubernaculum and spermatogenesis, involve extensive remodeling of the extra-cellular matrix (ECM) which is achieved by a tight balance of metalloproteinases and their inhibitors. Previous studies have indicated that metalloproteinase MT1-MMP plays an active role in testicular descent and MMP2 plays an important role in spermatogenesis [18]–[20]. Another member of the Adamts family of proteins, Adamts10, has been recently described as being expressed during the later stages of mouse spermatogenesis, incorporated into the acrosomal domain of developing spermatids and suggested to be important for sperm adhesion to the zona pellucida during fertilization [21].…”

Section: Discussionmentioning

confidence: 99%

Cryptorchidism and Infertility in Rats with Targeted Disruption of the Adamts16 Locus

et al. 2014

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A Disintegrin And Metalloproteinase with ThromboSpondin motifs16 (ADAMTS-16) is a member of a family of metalloproteinases. Using a novel zinc-finger nuclease based gene-edited rat model harboring a targeted mutation of the Adamts16 locus, we previously reported this gene to be linked to blood pressure regulation. Here we document our observation with this model that Adamts16 is essential for normal development of the testis. Absence of Adamts16 in the homozygous Adamts16mutant males resulted in cryptorchidism and male sterility. Heterozygous Adamts16mutant males were normal, indicating that this is a recessive trait. Testes of homozygous Adamts16mutant males were significantly smaller with significant histological changes associated with the lack of sperm production. Temporal histological assessments of the testis demonstrated that the seminiferous tubules did not support active spermatogenesis, but progressively lost germ cells, accumulated vacuoles and did not have any sperm. These observations, taken together with our previous report of renal abnormalities observed with the same Adamts16mutant rats, suggest an important mechanistic link between Adamts16 and the functioning of the male genitourinary system.

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Section: Discussionmentioning

confidence: 99%

Cryptorchidism and Infertility in Rats with Targeted Disruption of the Adamts16 Locus

et al. 2014

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“…The swelling and migration of the male gubernaculum with relaxation of the cranial suspensory ligament in the process of testicular descent allow testes to normally move from the posterior abdominal wall to the internal inguinal ring (Hutson 1985). The extracellular matrix remodelling in/around the rodent gubernaculum has been found necessary for its migration through the inguinal fat pad with the help of matrix metalloproteinases (Churchill et al 2011). Therefore, a mutated MID1IP1 could affect microtubule stabilization and then cause abnormal extracellular matrix remodelling in/around gubernaculum.…”

Section: Discussionmentioning

confidence: 99%

“…MID1IP1 has also been identified associated with microtubule stabilization in Atlantic salmon (Bower & Johnston 2010). The extracellular matrix remodelling in/around the rodent gubernaculum has been found necessary for its migration through the inguinal fat pad with the help of matrix metalloproteinases (Churchill et al 2011). They are the components for cytoskeleton internally and also for the extracellular matrix externally.…”

Section: Veeramachaneni 2007) Previous Studies Have Shownmentioning

confidence: 99%

A genome‐wide association study for canine cryptorchidism in Siberian Huskies

Xiao

Onteru

Saatchi

et al. 2013

J Animal Breeding Genetics

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Cryptorchidism is a condition whereby one or both testes fail to descend into the scrotal sac. Here, we performed a genome-wide association study (GWAS) with both a case-control analysis using the GEMMA software accounting for population structure and a BayesB approach in the GenSel software applied to every 1 Mb window of SNPs or haplotypes. The haplotypes were constructed from a genealogical tree using the population of 204 Siberian Huskies. The BayesB analyses identified six putative genomic candidate regions on CFA6, 9, 24, 27 and X. These regions explained a high percentage of genetic variance when compared with other genomic regions. The positional candidate genes Q9TSI5_CANFA (matrix metalloproteinase 9 precursor) on CFA24, ADAMTS20 (ADAM metallopeptidase with thrombospondin type 1 motif, 20) on CFA27 and MID1IP1 (MID1 interacting protein 1) on CFAX are known to be functionally related to extracellular matrix remodelling, which might be important for gubernaculum elongation and thus interrupting normal testicular descent. Further mutation screening in these candidate regions on CFA6, 9, 24, 27 and X is needed. Next generation sequencing will help to uncover rare variants associated with cryptorchidism in this dog population.

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“…The reduced swelling that we observed in the LE/orl gubernaculum herein and in prior studies (21, 23) may account for differences in its biomechanical properties. In a prior study using histological sections, matrix metalloproteinase (MMP)-expression was reported in cells adjacent to the inverting perinatal rat gubernaculum, suggesting that active ECM remodeling may facilitate gubernacular motility (61). Areas of clearing that we observed in the region between the central mesenchyme and peripheral muscle layers may be comparable to previous anatomical studies of the human fetus, which revealed loosening of the connections between the gubernaculum and surrounding cremaster-lined inguinal canal just prior to testicular descent (62).…”

Section: Discussionmentioning

confidence: 99%

Regional Variation in Androgen Receptor Expression and Biomechanical Properties May Contribute to Cryptorchidism Susceptibility in the LE/orl Rat

et al. 2018

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Background: The process of testicular descent requires androgen and insulin-like 3, hormones secreted by fetal Leydig cells. Knowledge concerning distinct and common functions of these hormones in regulating development of the fetal gubernaculum remains limited and/or conflicting. The current studies were designed to better define characteristics of androgen receptor (AR) expression, function and regulation, as well as the biomechanical properties of normal and cryptorchid gubernaculum during fetal development.Methods: We studied fetal gubernacula from Long Evans outbred (LE/wt) rats and an inbred (LE/orl) strain with an inherited form of cryptorchidism associated with an AR signaling defect. Gubernacular cells or whole organs obtained from LE/wt and LE/orl fetal gubernacula underwent AR immunostaining and quantitative image analysis. The effects of dihydrotestosterone (DHT) on AR expression, muscle fiber morphology, hyaluronan (HA) levels and glycosaminoglycan (GAG) content were measured in LE/wt gubernacula. Finally, the spatial mechanics of freshly harvested LE/wt and LE/orl fetal gubernacula were compared using micropipette aspiration.Results: AR is expressed in the nucleus of mesenchymal core, tip and cord cells of the embryonic (E) day 17 and 21 fetal gubernaculum, and is enhanced by DHT in primary cultures of gubernacular mesenchymal cells. Enhanced AR expression at the tip was observed in LE/wt but not LE/orl gubernacula. In in vitro studies of whole mount fetal gubernaculum, DHT did not alter muscle fiber morphology, HA content or GAG production. Progressive swelling with reduced cellular density of the LE/wt gubernaculum at E19–21 was associated with increased central stiffness in LE/wt but not in LE/orl fetuses.Conclusions: These data confirm nuclear AR expression in gubernacular mesenchyme with distal enhancement at the tip/cord region in LE/wt but not LE/orl rat fetuses. DHT enhanced cellular AR expression but had no major effects on muscle morphology or matrix composition in the rat fetal gubernaculum in vitro. Regional increased stiffness and decreased cell density between E19 and E21 were observed in LE/wt but not LE/orl fetal gubernacula. Developmental differences in cell-specific AR expression in LE/orl fetal gubernacula may contribute to the dysmorphism and aberrant function that underlies cryptorchidism susceptibility in this strain.

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Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent?

Cited by 18 publications

References 15 publications

Cryptorchidism and Infertility in Rats with Targeted Disruption of the Adamts16 Locus

Cryptorchidism and Infertility in Rats with Targeted Disruption of the Adamts16 Locus

A genome‐wide association study for canine cryptorchidism in Siberian Huskies

Regional Variation in Androgen Receptor Expression and Biomechanical Properties May Contribute to Cryptorchidism Susceptibility in the LE/orl Rat

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