Uterine Tumors Resembling Ovarian Sex Cord Tumors in Four Baboons ( Papio spp.).

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare uterine neoplasms that exhibit prominent sex cord-like differentiation. The authors describe 4 cases of UTROSCTs that were identified as incidental lesions in female baboons. All baboons were in good body condition. One animal had a 2-mm-diameter yellow-tan mass in the uterine body along the attachment of the left broad ligament; the other 3 did not have any gross lesions in the uterus. Histologically, the myometrium contained multifocal well-demarcated neoplasms composed of cuboidal to columnar cells arranged in variable arrangements of sheets, nests, cords, trabecular, and retiform patterns that occasionally formed Call-Exner-like bodies. In all cases, the neoplastic cells were diffusely positive for WT-1 and negative for calretinin, CD99, and desmin. One case was positive for inhibin and CD10. To the best of the authors' knowledge, this is the first report of UTROSCTs in nonhuman primates and in the veterinary literature.

A case report of ovotesticular disorder of sex development (OT-DSD) in a baboon (Papio spp.) and a brief review of the non-human primate literature.

Disorders of sexual development are rare in non-human primates. We report a case of true hermaphroditism in a 19-year-old, nulliparous, female baboon (Papio spp.). At necropsy, the animal was obese with adequate muscle mass and hydration. Reproductive organs appeared normal with the exception of 2 firm nodular structures in the myometrium (1-1.5 cm diameter) and a thickened, dark endocervical mucosa. Histologically, both gonads were ovotestes and contained discrete areas of ovarian and testicular tissue. There were follicles in various stages of development surrounded by ovarian stroma. Other areas contained hypoplastic seminiferous tubules lined by Sertoli cells, but lacked germ cells and spermatozoa. The uterine lesions were consistent with adenomyosis and cystic endometrial hyperplasia. Cervical lesions were consistent with atypical glandular hyperplasia and squamous metaplasia with dysplasia. We report the first case of ovotesticular disorder of sexual development (OT-DSD), or true hermaphroditism in a baboon.

Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing.

The transmembrane recognition complex (TRC40) pathway mediates the insertion of tail-anchored (TA) proteins into membranes. Here, we demonstrate that otoferlin, a TA protein essential for hair cell exocytosis, is inserted into the endoplasmic reticulum (ER) via the TRC40 pathway. We mutated the TRC40 receptor tryptophan-rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective TA protein insertion. Wrb disruption reduced otoferlin levels in hair cells and impaired hearing, which could be restored in zebrafish by transgenic Wrb rescue and otoferlin overexpression. Wrb-deficient mouse inner hair cells (IHCs) displayed normal numbers of afferent synapses, Ca2+ channels, and membrane-proximal vesicles, but contained fewer ribbon-associated vesicles. Patch-clamp of IHCs revealed impaired synaptic vesicle replenishment. In vivo recordings from postsynaptic spiral ganglion neurons showed a use-dependent reduction in sound-evoked spiking, corroborating the notion of impaired IHC vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its ER targeting and caused an auditory synaptopathy. We conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells.

The zebrafish pinball wizard gene encodes WRB, a tail-anchored-protein receptor essential for inner-ear hair cells and retinal photoreceptors.

KEY POINTS: The zebrafish pinball wizard (pwi) mutant is deaf and blind. The pwi phenotype includes a reduced auditory startle response and reduced visual evoked potentials, suggesting fatigue of synaptic release at ribbon synapses in hair cells and photoreceptors. The gene defective in the pwi mutant is WRB, a protein homologous to the yeast protein Get1, which is involved in the insertion of 'tail-anchored' membrane proteins. Many tail-anchored proteins are associated with synaptic vesicles, and both vesicles and synaptic ribbons are reduced in synaptic regions of hair cells in pwi. Abnormal processing of synaptic vesicle proteins important for ribbon synapses can explain the pwi phenotype. ABSTRACT: In a large-scale zebrafish insertional mutagenesis screen, we identified the pinball wizard (pwi) line, which displays a deafness and blindness phenotype. Although the gross morphology and structure of the pwi larval inner ear was near normal, acoustic startle stimuli evoked smaller postsynaptic responses in afferent neurons, which rapidly fatigued. In the retina, similarly, an abnormal electroretinogram suggested reduced transmission at the photoreceptor ribbon synapse. A functional deficit in these specialized synapses was further supported by a reduction of synaptic marker proteins Rab3 and cysteine-string protein (CSP/Dnajc5) in hair cells and photoreceptors, as well as by a reduction of the number of both ribbons and vesicles surrounding the ribbons in hair cells. The pwi gene encodes a homologue of the yeast Get1 and human tryptophan-rich basic (WRB) proteins, which are receptors for membrane insertion of tail-anchored (TA) proteins. We identified more than 100 TA proteins expressed in hair cells, including many synaptic proteins. The expression of synaptobrevin and syntaxin 3, TA proteins essential for vesicle fusion, was reduced in the synaptic layers of mutant retina, consistent with a role for the pwi/WRB protein in TA-protein processing. The WRB protein was located near the apical domain and the ribbons in hair cells, and in the inner segment and the axon of the photoreceptor, consistent with a role in vesicle biogenesis or trafficking. Taken together, our results suggest that WRB plays a critical role in synaptic functions in these two sensory cells, and that disrupted processing of synaptic vesicle TA proteins explains much of the mutant phenotype.