Wnt signalling in testicular descent: a candidate mechanism for cryptorchidism in Robinow syndrome.

Background/aims: Robinow syndrome is caused by mutations in Wnt-5a or its receptor Ror2 and can lead to cryptorchidism, though the mechanisms are unclear. Wnt-5a knock-out mice fail to undergo gubernacular swelling, similar to insulin-like hormone 3 (INSl-3) knock-out mice. We aimed to characterise Wnt-5a and Ror2 expression in rat gubernacula to better understand how Wnt-5a signalling affects testicular descent.

Regression of the mammary branch of the genitofemoral nerve may be necessary for testicular descent in rats.

Purpose: Inguinoscrotal testicular descent has been proposed to occur via sensory fibers of the sexually dimorphic genitofemoral nerve, which release a neurotransmitter, calcitonin gene related peptide, to guide the migrating gubernaculum into the scrotum. We hypothesize that androgen mediated regression of the genitofemoral nerve mammary branch is necessary for inguinoscrotal descent in rats. We compared the spatiotemporal development of the genitofemoral nerve in control and antiandrogen treated rats.

The effect of flutamide on expression of androgen and estrogen receptors in the gubernaculum and surrounding structures during testicular descent.

Background/purpose: Inguinoscrotal testicular descent is controlled by androgens between embryonic days E16-19, but androgen receptor (AR) and estrogen receptor (ER) locations are unknown. We aimed to find AR, ERα, and ERβ in the gubernaculum and inguinal fat pad (IFP) in normal rats and after flutamide treatment.

Methods: Sprague-Dawley timed-mated rats were injected with flutamide (75 mg/kg body weight/5% ethanol + oil) on E16-19 or vehicle alone.

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

Purpose: Cryptorchidism is the most common male congenital abnormality. The rodent gubernaculum steers the testis from abdomen to scrotum postnatally by eversion and migration through the developing inguinal fat pad (IFP). We hypothesize that extracellular matrix remodeling in/around the gubernaculum is necessary for eversion and migration and is permitted by timed IFP maturation and aimed to examine regional development and matrix metalloproteinase (MMP) content.

Gubernacular development in the mouse is similar to the rat and suggests that the processus vaginalis is derived from the urogenital ridge and is different from the parietal peritoneum.

Background: Gubernacular development and testicular descent have been studied most extensively in rat models, but new transgenic mouse models require a deep understanding of normal mouse development so that results can be extrapolated to the human. We aimed to compare gubernacular anatomy during development in the mouse with that of the rat.

Methods: Time-mated mice (C57BL/6) and Sprague-Dawley rats were used to collect male fetuses at embryonic (E) days E13, E14, E15, E17, E18, and E19 and neonates at postnatal (P) days P0 and P2.

The development and anatomy of the gubernaculum in Hoxa11 knockout mice.

Background: The gubernaculum is central to testicular descent, with recent evidence suggesting that it elongates to the scrotum like a limb bud. Homeobox (Hox) genes involved in limb bud outgrowth are expressed within the gubernaculum. Mice with homozygous Hoxa11 gene deletions have bilateral cryptorchidism.

Gender differences in reduced substance P (SP) in children with slow-transit constipation.

Purpose: Adult slow-transit constipation (STC) occurs predominantly in females and is associated with low numbers of substance P (SP)-containing nerves in colonic circular muscle.

Aim: To determine if reduced SP nerves is female predominant in paediatric STC.

Methods: Children with STC were identified from records of more than 600 nuclear transit studies (NTS) and intestinal biopsies done for intractable chronic constipation between November 1998 and March 2009.

Growth of the rat gubernaculum in vitro and localisation of its growth centre.

Purpose: Recent studies suggest that testicular descent is accomplished by outgrowth of the gubernaculum from the abdominal wall. The tip of the gubernaculum has been proposed as the primary site of growth, similar to an embryonic limb bud. We aimed to determine the maximum site of growth in organ culture.

Evidence of a novel aggrecan-degrading activity in cartilage: Studies of mice deficient in both ADAMTS-4 and ADAMTS-5.

Objective: To characterize aggrecan catabolism and the overall phenotype in mice deficient in both ADAMTS-4 and ADAMTS-5 (TS-4/TS-5 Delta-cat) activity.

Methods: Femoral head cartilage from the joints of TS-4/TS-5 Delta-cat mice and wild-type mice were cultured in vitro, and aggrecan catabolism was stimulated with either interleukin-1alpha (IL-1alpha) or retinoic acid. Total aggrecan release was measured, and aggrecanase activity was examined by Western blotting using neoepitope antibodies for detecting cleavage at EGE 373-374 ALG, SELE 1279-1280 GRG, FREEE 1467-1468 GLG, and AQE 1572-1573 AGEG.

The anatomy of the cremaster muscle during inguinoscrotal testicular descent in the rat.

Background: Extrapolation of rat testicular descent studies to humans has been criticized because of anatomical differences of the cremaster muscle. Human cremaster is described as a thin strip rather than a large, complete sac as in rats, which is proposed to be more important in propelling the testis during descent. This study investigated cremaster muscle anatomy and ontogeny in both normal and cryptorchid rat models.

Cell membrane and mitotic markers show that the neonatal rat gubernaculum grows in a similar way to an embryonic limb bud.

Aim/background: How the gubernaculum guides the testis into the scrotum remains controversial, with various proposals from passive inversion to active growth. We aimed to determine if the gubernaculum contains an area of active proliferation, such as a "progress zone" in a growing embryonic limb bud, using a fluorescent cell membrane marker, 1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate [DiIC12(3)], to trace cell migration, and 5-bromodeoxyuridine (BUDR) (a thymidine analogue) as a mitotic marker.

Methods: Gubernacula were collected from neonatal male rats (n = 42, day 1-2, Sprague-Dawley) and cultured with calcitonin gene-related peptide (CGRP; 714 nmol/L).

Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair.

Aggrecan loss from cartilage in arthritis is mediated by aggrecanases. Aggrecanases cleave aggrecan preferentially in the chondroitin sulfate-2 (CS-2) domain and secondarily at the E(373) downward arrow(374)A bond in the interglobular domain (IGD). However, IGD cleavage may be more deleterious for cartilage biomechanics because it releases the entire CS-containing portion of aggrecan.

Does chemical sympathectomy alter the ontogeny of gubernacular migration in vivo?

Background: Testicular descent occurs in several stages, but the exact mechanism remains obscure. Sympathetic nerves have been proposed to have a role by a possible action on developing cremaster muscle, following observations of sympathetic dysfunction in cremaster from boys with cryptorchidism. This study aimed to see if chemical sympathectomy affected testicular descent in rats.

A new role for androgen in testicular descent: permitting gubernacular cell proliferation in response to the neuropeptide, calcitonin gene-related peptide.

Background/purpose: Cell proliferation at the gubernacular tip increases in response to exogenous calcitonin gene-related peptide (CGRP) during migration into the scrotum. Calcitonin gene-related peptide is contained in the masculinized sensory branches of the genitofemoral nerve. We tested the independent effects of chemical sensory nerve disruption and prenatal androgen blockade on the in vitro gubernacular proliferative response to CGRP.

ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro.

Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more 'aggrecanases' from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity.

Gubernacular cell division in different rodent models of cryptorchidism supports indirect androgenic action via the genitofemoral nerve.

Purpose: The role of the "gubernaculum" in testicular descent remains controversial. Androgens are proposed to act indirectly by the genitofemoral nerve (GFN) releasing calcitonin gene-related peptide. The authors studied the effects of sensory nerve ablation and androgen blockade on mitosis in the gubernacular tip to determine whether androgens act directly or indirectly.

Role of the gubernacular bulb in cremaster muscle development of the rat.

The role of the gubernaculum during the inguino-scrotal phase of testicular descent remains controversial. Some authors propose involution and eversion while others suggest active migration, although the site of growth is unknown. We aimed to determine whether the gubernacular bulb is actively proliferating or regressing during inguino-scrotal testicular descent in the rat.