Disease relevance of Utp14b

• The Utp14b is specifically expressed in male germ cells and, when mutated in the jsd (juvenile spermatogonial depletion) mouse, results in early spermatogenic arrest and male infertility [1].
• In irradiated LBNF1 rats, which have a block in spermatogonial differentiation similar to that in jsd mutant mice, unilateral cryptorchidism produced a small but significant increase in the percentage of differentiated tubules [2].
• Male mice homozygous for the mutant juvenile spermatogonial depletion (jsd) gene show spermatogonial arrest and an elevated intratesticular testosterone level like many other experimental infertility models such as those with iradiation- or chemotherapy-induced testicular damage [3].
• The onset of such azoospermia was investigated by histologic analysis of sections of testes from jsd/jsd mice [4].
• Furthermore, the defect in B6-jsd/jsd spermatogonia is not in their ability to proliferate, but in their differentiation and may result from their hypersensitivity to high concentrations of androgen in the testis [5].

High impact information on Utp14b

• To our knowledge, Utp14b is the first protein-coding retrogene to be linked to a recessive mammalian phenotype [6].
• This gene, Utp14b, evidently arose through reverse transcription of an mRNA from an X-linked gene and integration of the resulting cDNA into an intron of an autosomal gene, whose promoter and 5' untranslated exons are shared with Utp14b [6].
• We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive spermatogenic defect mapped to mouse chromosome 1 (refs. 1,2) [6].
• We localized jsd to a 272-kb region and resequenced this area to identify the underlying mutation: a frameshift that severely truncates the predicted protein product of a 2.3-kb genomic open reading frame [6].
• In jsd homozygotes, which lack a functional copy of Utp14b, insufficient production of rRNA quickly leads to a cessation of spermatogenesis [7].

Biological context of Utp14b

• In the mouse, Utp14b is a retrogene transposed to an intron of Acsl3 (long-chain-fatty-acid coenzyme A ligase 3) on mouse chromosome 1 [1].
• This feature facilitated mapping the jsd gene to the centromeric end of chromosome 1; the gene order is jsd-Isocitrate dehydrogenase-1 (Idh-1)-Peptidase-3 (Pep-3) [8].
• Confirmation that mUtp14b underlies the jsd phenotype was obtained by transgenic bacterial artificial chromosome (BAC) rescue [7].
• In homozygous jsd mice in a hybrid background (C3HxB6) that were identified with microsatellite markers, the percentage of tubules showing differentiating germ cells [tubule differentiation index (TDI)] rapidly decreased after 7 weeks of age with a correlative increase in the intratesticular testosterone (ITT) levels [9].
• The region of mouse chromosome 1 that carries other genes known to have homologs on human chromosome 2q includes the jsd locus (for juvenile spermatogonial depletion) [10].

Anatomical context of Utp14b

• Unlike mouse Utp14b, which is only expressed in the male germ line, human UTP14c is expressed in testis and ovary, which is consistent with having a gonad-specific function [1].
• We hypothesize the jsd/jsd male may be deficient in proliferative signals from Sertoli cells that are needed for spermatogenesis [8].
• Analysis of testicular histology from jsd/jsd mice aged 3-10 wk revealed that these mutant mice experience one wave of spermatogenesis, but fail to continue mitotic proliferation of type A spermatogonial cells at the basement membrane [8].
• Analyses of serum hormones of jsd/jsd males showed that testosterone levels were normal at all ages--a finding corroborated by normal seminal vesicle and vas deferens weights, whereas serum follicle-stimulating hormone levels were significantly elevated in mutant mice from 4 to 20 wk of age [8].
• The recessive juvenile spermatogonial depletion (jsd) mutation results in a single wave of spermatogenesis, followed by failure of type A spermatogonia to differentiate, resulting in adult male sterility [7].

Associations of Utp14b with chemical compounds

• Treatment with retinol failed to alter the loss of spermatogenesis in jsd/jsd mice [8].
• To delineate the role of testosterone (T) in spermatogonial arrest, we gave 7.6-week-old jsd mice exogenous T and/or the androgen receptor antagonist flutamide with or without GnRH antagonist for 4 weeks [9].
• Although spermatogonia were indeed present in adult jsd-fshb double-mutant mice and were capable of differentiation after androgen deprivation, these mice had a tubule differentiation index of 0%, ruling out the possibility that endogenous FSH inhibited spermatogonial differentiation in jsd mice [11].
• Stimulation of spermatogonial differentiation in juvenile spermatogonial depletion (jsd) mutant mice by gonadotropin-releasing hormone antagonist treatment [12].
• To determine if jsd spermatogonia are able to develop in a permissive seminiferous environment, jsd germ cells were transplanted into W/W(v) and busulfan-treated C57BL/6 animals [13].

Other interactions of Utp14b

• Our data define a critical jsd interval of approximately 0.4 cM at 49 cM on mouse chromosome 1, between D1Mit215 and 257SP6 [14].
• The results indicate that T inhibits the ability of spermatogonia to differentiate in jsd mice through an androgen receptor-mediated process [9].
• The testis weight and the degree of spermatogenesis in cryptorchidized normal (jsd/+) and jsd mutant mice were almost identical [2].

Analytical, diagnostic and therapeutic context of Utp14b

• Furthermore, we successfully rescued male sterility in jsd mice by subsequent intracytoplasmic sperm injection using the elongated spermatids induced by the programmed hormone therapy [3].
• The possibility that the mutation in jsd involves the INH alpha or INH beta B gene was investigated by Southern blotting of DNA from jsd/jsd mice, and no major deletions or rearrangements were detected [10].
• We used cDNA microarrays and representational difference analysis to identify genes that are expressed in the testis of the jsd/jsd mutant mouse, which contains only type A spermatogonial germ cells and Sertoli cells, but not in the testis of the W/W(v) mutant mouse, where Sertoli cells but few germ cells are present [15].
• The data demonstrate that up to 7 mo after transplantation of normal germ cells, jsd seminiferous tubules are capable of supporting spermatogenesis [13].

References