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At least 19 recordsLinked to original sources
PubMed2026

Post-translational modification of proteins in the human testis development pathway.

BACKGROUND: The foetal testes produce the androgens necessary to masculinise the developing embryo and support the maturation of germ cells, that will eventually develop into sperm, thus ensuring future reproductive capacity. The testes develop from the bi-potential gonads in a highly orchestrated process resulting in the differentiation of a complex tissue with multiple cellular lineages. While recent transcriptomic and chromatin-based analyses of human foetal testes have provided an unprecedented level of insight into signalling pathways activated during this process, proteomic studies of the human foetal gonads remain limited. Proteins are active molecules and post-translational modification (PTM) of proteins influences protein activity, stability and localisation. Studies have shown that PTMs regulate critical proteins in testis development, and their disruptions are implicated in congenital disorders including differences of sex development (DSD), in which sex development is atypical. Despite this, the role and regulation of protein PTM during human testis development remains poorly understood due to limited access to human foetal gonadal tissue, a paucity of large-scale proteomics studies, and a lack of robust of human gonad in vitro models. OBJECTIVE AND RATIONALE: This review aims to provide a comprehensive analysis of validated PTMs affecting proteins critical for testicular development. We discuss PTMs with evidence for a role in normal testis development, and highlight those disrupted in DSD. We review emerging techniques, including proteomic technologies and organ modelling systems that may advance our understanding of PTMs in foetal testis development. We discuss challenges that have restricted the application of these technologies and how overcoming these will significantly improve our understanding of testis development and disease, diagnostics and patient outcomes. SEARCH METHODS: We searched PubMed and the University of Melbourne library for peer-reviewed English-language studies using keywords such as phosphorylation, SUMOylation, acetylation, ubiquitination alongside each protein of interest. PTM sites in proteins involved in testis development were identified using the PhosphoSitePlus database focusing those confirmed in in vitro or animal model studies. ClinVar and the Human Gene Mutation Database were used to identify patient variants that may disrupt PTM sites. OUTCOMES: Our review finds that proteins required for human foetal testis development are subject to extensive PTM. Several PTM sites and PTM-mediated pathways [e.g. MAPK (mitogen-activated protein kinase) pathway] are disrupted in patients with DSD or related conditions. While recent advances in proteomics technologies hold considerable promise, their application to human foetal gonads has been constrained by technical, ethical, and logistical challenges. Encouragingly, emerging high-sensitivity and low-input technologies, alongside stem cell-based approaches, offer viable pathways to overcoming these barriers. WIDER IMPLICATIONS: The relationship between gene regulation, protein expression, and cellular outcome is inherently non-linear, shaped by additional regulatory layers-most notably PTMs. The contribution of PTMs to human testis development in both typical and atypical contexts is a major knowledge gap. Addressing this gap has broad clinical and biological relevance: it may help improve genetic diagnosis or shed light on how proteins or pathways critical for testis development respond to environmental signals-an increasingly pressing question as declining global fertility rates bring testicular function under greater scrutiny. REGISTRATION NUMBER: N/A.

Humans↗
PubMed2026

Mismatch repair protein MLH1 controls testis development by regulating the Hippo-YAP signaling pathway.

DNA mismatch repair (MMR) maintains genomic stability, and defects in MMR genes such as MLH1 and MSH2 predispose to cancer. Unlike other MMR components, MLH1 has unexplained roles in development, as Mlh1-deficient male mice exhibit severe testicular hypoplasia and sterility. Here, we uncover that MLH1 regulates testis development through the Hippo-Yes-associated protein (YAP) pathway. MLH1 directly binds YAP via its C-terminal domain and the WW domains of YAP, competitively inhibiting LATS1-mediated YAP phosphorylation. This interaction stabilizes YAP by suppressing ubiquitination and promotes its nuclear translocation dependent on MLH1's nuclear localization signal. Additionally, MLH1 facilitates YAP-TEAD complex formation, enabling expression of testicular development genes, including Wt1, Sox9, and Ctgf. These functions are independent of the MMR activity of MLH1. Mlh1-deficient mice show elevated YAP phosphorylation, reduced target gene expression, and impaired proliferation in developing testes. Pharmacological inhibition of the Hippo pathway kinases MST1/2 partially rescues testis hypoplasia in Mlh1-/- mice. These findings establish MLH1 as a Hippo pathway regulator and resolve its long-standing role in male gonad development.

Male↗
PubMed1976

[Tubular structure and germ cell distribution of cryptorchid or normal testes in early childhood (author's transl)].

INTRODUCTION: Many recent publications have demonstrated that the cryptorchid testicle (and, to a lesser extent, the descended partner) are progressively injured from the second year of life onwards. Do these injuries occur in an organ which has been healthy up to this time or are they superimposed on a structurally abnormal testicle? In order to answer this, parts of cryptorchid testicles, of the descended partners, and of normal testicles were compared by histological examination of serial sections. MATERIAL AND METHODS: Parts of four testes from children aged 4-7 months (2 specimens obtained by biopsy and 2 from autoptic material) and parts of four testes from children 1 1/2 years old (2 obtained by biopsy and 2 from autoptic material) were examined. The biopsies were fixed in Stieve's fixative. Tissue samples from clinically healthy children who had died suddenly were fixed in 4% formalin. The tissue was embedded in paraffin and sectioned serially; 6 mum sections were stained with HE. The spermatogonia in each cross-section and in each oblique section of a same tubule were counted and the counts of the latter were adjusted to a cross-section 50-60 mum in diameter. This counting technique did not alter the density of spermatogonia. The graphs present data on the density of spermatogonia through the lengths of the tubules examined and demonstrate tubular branching and blind ends. In the first year of life the cryptorchid testis and its descended partner showed repeated long sections lacking spermatogonia in the same tubule, whereas in normal testes the spermatogonia were more evenly distributed. The cryptorchid testis showed increased tubule branching in the areas examined. In the second year of life the tubules of the cryptorchid testis and its descended partner manifest areas free of germ cells, increased branching, and blind ends. The cryptorchid testis also had a tubule completely free of spermatogonia. The germ cell-free parts were always associated with a smaller tubule diameter than normal. The normal testes did not disclose increased branching or spermatogonium-free areas within similar lengths of tubules and showed an even distribution of spermatogonia. DISCUSSION: The different distribution of spermatogonia within the tubules and the increased branching of the tubules in cryptorchid testes indicate a previous disturbance of testis development.

Age Factors↗
PubMed2026

Both L-Lactyl and D-Lactyl Enantiomers Modify Histones in Mouse Testis.

Dynamic histone posttranslational modifications are crucial to precisely orchestrate gene expression programs. The recently discovered histone lysine lactylation has already been explored in various pathological contexts, but less in normal tissues. This modification exists as two enantiomers, L- and D-lactylation; the former may more likely modify histones due to abundant L-lactate produced by glycolysis. Here, we report the identification by proteomics of L- and D-lactylation on lysines of histones H3 and H4 in mouse testis. We developed a targeted proteomic analysis of histone peptides using synthetic sequences modified by L- or D-lactyl, to acquire reliable identification and quantification data. Some histone peptides bearing either enantiomer are separated by reversed-phase chromatography. Interestingly, despite the fact that L-lactate is much more abundant than D-lactate in mouse testis, we estimated abundance ratios of L-over D-lactylation to lie between 0.4 and 1.6 on seven residues of histones H3 and H4. Next, targeted proteomic analyses were performed on histones extracted from meiotic and postmeiotic male germ cells (spermatocytes and round spermatids, respectively), which are known to use L-lactate as a main source of energy. Nonetheless, residues 18 and 23 of histone H3 (H3K18 and H3K23) were reliably quantified and shown to harbor balanced amounts of both enantiomers. The stoichiometry of lactylation is low over the whole sequence of H3 and H4, representing about 0.01 to 0.44%: this contrasts with acetylation which exists at up to 25 to 35% relative abundances on some N-terminal lysines. Yet, lactylation appears to be more abundant than acetylation on the C-terminal half of H3 and H4, where the latter modification is scarce. Collectively, our results suggest a mechanism producing a mixture of the two enantiomers of lactate, or of a more direct substrate for lactylation, that leads to the modification of histones by L- and D-lactylation.

Animals↗
PubMed1976

Cancer of the undescended or maldescended testis.

An analysis of 45 cryptorchids (by history or examination) with a testicular cancer treated at Memorial Hospital, between 1934 and 1973, is presented. Twenty-five patients had the cryptorchid state repaired at ages four to 27 years, either spontaneously or by orchiopexy or hormonal therapy. Ipsilateral (24) or contralateral (one) intrascrotal testis tumors developed four to 47 years later. Twenty cryptorchid patients presented with ipsilateral inguinal (eleven), abdominal (seven), or contralateral intrascrotal (two) tumors. There were 18 pure seminomas, 17 embryonal carcinomas, nine teratocarcinomas, and one reticulum cell sarcoma. Five year survival rates as estimated by the product-limit method were 60% for the unrepaired cases and 41% for the repaired cases. The survival seems to follow histologic type and anatomical stage, whether the testis is within the scrotum or not. Five year survival similarly estimated was 78% in the seminomas and 29% in the other tumors. Twelve of thirteen survivors (including nine with seminoma) received postoperative irradiation to the regional lymphatics and eleven were without recurrent tumor for periods ranging from six to 28 years.

Adolescent↗
PubMed1977

Congenital testicular lymphangiectasis.

Testicular lymphangiectasis are described for the first time in a patient with bilateral inguinal cryptorchidism. A great number of irregular lymphatic channels was observed within the parenchyma and the tunica vasculosa in both testes. Large and numerous anastomosis between the lymphatic vessels of these two areas could also be seen. The MTD and the TFI of the left testis were normal. Both parameters were very low in the right testis. The association of this fact with the greater development of the lymphatic vessels in this testis strongly supports the idea that testicular lymphangiectasis interfere mechanically with the testis tubular development.

Biopsy↗
PubMed1976

Malignant germ cell tumor in situ in a cryptorchid testis.

A case of a malignant undifferentiated germ cell tumor in situ of an undescended testis diagnosed by needle biopsy is described. Four similar cases have been so far recorded in the literature, all of them in the infertile men with normally descended descended testes. Two of them developed embryonal carcinoma of testis 4 1/2 later and one had a concomitant seminoma. In a high-risk group of patients (atrophic testis, cryptorchidism), a needle biopsy of a testicle may discover malignancy in its very early phase of development (Stage 0), at which time an orchiectomy alone may be a curative treatment.

Adult↗
PubMed1976

Torsion of the testis and allied conditions.

In 15 years at Bristol there have been 293 cases of torsion of the testis, 55 cases of torsion of a testicular appendage and 5 cases of testicular ischaemia due to other causes. The risk of a male developing torsion of the testis or its appendix by the age of 25 is about 1 in 160. Both conditions occurred primarily in adolescents, but among prepubertal boys torsion of an appendage was as common as torsion of a normally descended testis. There was a slight left-sided preponderance in testicular torsion, more marked in torsion of the appendages; the incidence of bilateral torsion was 2-0 and 1-8 per cent respectively. The clinical features and differential diagnosis of the two conditions are compared. Torsion of a testicular appendage is the most commonly misdiagnosed scrotal lesion, the preoperative diagnosis being correct in only 11 per cent of cases compared with 90 per cent for torsion of the testis. Twenty-one cases of recurrent torsion underwent prophylactic bilateral orchidopexy. There were 20 cases of torsion of undescended testes, with a salvage rate of only 20 per cent. The overall testicular survival rate was 55-3 per cent. Viability depends upon the possibility of spontaneous reduction, the preoperative delay after the onset of symptoms, the degree of torsion of the cord and the length of follow-up in doubtful cases. Urgent scrotal exploration is advised in every case of acute testicular pain unless there is overwhelming evidence of epididymoorchitis. Exploration of the opposite side is mandatory in torsion of the testis and advisable in torsion of an appendage.

Adolescent↗
PubMed1977

Carcinoma in situ of the ectopic testis.

A young man with a palpable ectopic testis underwent right testis biopsy and orchiopexy. Since histological findings of the biopsy specimen revealed an unsuspected intratubular carcinoma in situ and evidence of diminished spermatogenic potential, an inguinal orchiectomy was done. This appears to be the first reported case of a tumor of this type developing in an undescended testis.

Adult↗
PubMed2024

Consider CUX1 variants in children with a variation of sex development: a case report and review of the literature.

BACKGROUND: The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented. CASE PRESENTATION: The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4-10 of the CUX1 gene. CONCLUSIONS: Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development.

Humans↗
PubMed1976

An equine cryptorchid with testicular and ovarian tissues.

Cytogenetic and histological studies were carried out on an intersex horse which was diagnosed clinically as a cryptorchid. Surgery confirmed the horse to be a bilateral abdominal cryptorchid and histological examination revealed ovarian tissue associated with the left epididymis. Chromosome analysis of cultured cells from testicular tissue, ovarian tissue and skin revealed 64-XX and 64-XY make-up, the left gonad containing a greater preponderance of XX cells over XY cells. The external characteristics and behaviour of the horse were indistinguishable from that of a "routine" cryptorchid. Other cases of equine intersexes are reviewed and theories for the discrepancies between genetic, gonadal and phenotypic sex are discussed.

Animals↗
PubMed1976

Effect of unilateral and bilateral castration and cryptorchidism on serum gonadotrophins in the rat.

The effects of unilateral and bilateral cryptorchidism and castration on serum concentrations of testosterone, FSH and LH in adult male rats were examined. The results provide no evidence for compensatory growth or development of the remaining scrotal testes up to 32 days after unilateral castration, although the scrotal testis of unilaterally cryptorchid rats showed enlargement when compared with those of control rats (P less than 0 - 05) at 32 days. Unilateral treatments had few significant effects on serum hormones, but testosterone was increased on day 4 (P less than 0 - 05) in unilaterally cryptorchid rats and on day 32 (P less than 0 - 05) in unilaterally castrated rats, compared with controls, and FSH levels were higher in unilaterally castrated rats on day 16 (P less than 0 - 05). Bilateral cryptorchidism caused an increase in serum FSH within 4 days (P less than 0 - 05) and in serum LH by 8 days (P less than 0-05) after surgery, with both hormones reaching levels double those found in control rats (P less than 0 - 01) by day 16, while testosterone levels were maintained at or above control values. Bilateral castration resulted in a marked decrease in testosterone levels (P less than 0 - 01) and a sharp increase in serum gonadotrophins. FSH had nearly doubled (P less than 0 - 01) and LH had increased fourfold (P less than 0 - 01) 4 days after castration, their levels reaching 773% (LH) and 287% (FSH) of control values by 32 days (P less than 0 - 01). The observations support the hypothesis of a separate, testosterone-independent feedback system of the testis on the hypophysis.

Animals↗
PubMed1977

[Sexual development of boys, treated surgically for dystopia of testicles (author's transl)].

A clinical follow-up examination was made in a group of 208 children and adolescents who had undergone surgical treatment for congenital cryptorchid testis (unilateral or bilateral) between 2 and 10 years before. The puberal growth and maturing process of the primary and secondary sex characteristics of this morbidity group was compared to that of normal juveniles. The examination was made according to clinical criteria: length and circumference of the penis, volume of testes, general development of the genitals, pubic hair. Compared to normal juveniles, the genital development of the children and adolescents of the follow-up examinations series was retarded.

Adolescent↗