Abstract
The Leprecan protein family which includes the prolyl 3-hydroxylase enzymes (P3H1, P3H2, and P3H3), the closely related cartilage-associated protein (CRTAP), and SC65 (Synaptonemal complex 65, aka P3H4, LEPREL4), is involved in the post-translational modification of fibrillar collagens. Mutations in CRTAP, P3H1 and P3H2 cause human genetic diseases. We recently showed that SC65 forms a stable complex in the endoplasmic reticulum with P3H3 and lysyl hydroxylase 1 and that loss of this complex leads to defective collagen lysyl hydroxylation and causes low bone mass and skin fragility. Interestingly, SC65 was initially described as a synaptonemal complex-associated protein, suggesting a potential additional role in germline cells. In the present study, we describe the expression of SC65, CRTAP and other Leprecan proteins in postnatal mouse reproductive organs. We detect SC65 expression in peritubular cells of testis up to 4 weeks of age but not in cells within seminiferous tubules, while its expression is maintained in ovarian follicles until adulthood. Similar to bone and skin, SC65 and P3H3 are also tightly co-expressed in testis and ovary. Moreover, we show that CRTAP, a protein normally involved in collagen prolyl 3-hydroxylation, is highly expressed in follicles and stroma of the ovary and in testes interstitial cells at 4 weeks of age, germline cells and mature sperm. Importantly, CrtapKO mice have a mild but significant increase in morphologically abnormal mature sperm (17% increase compared to WT). These data suggest a role for the Leprecans in the post-translational modification of collagens expressed in the stroma of the reproductive organs. While we could not confirm that SC65 is part of the synaptonemal complex, the expression of CRTAP in the seminiferous tubules and in mature sperm suggest a role in the testis germ cell lineage and sperm morphogenesis.
Highlights
The Leprecan family of proteins is composed of five members that mostly localize to the endoplasmic reticulum (ER)
Mutations in any one of the genes coding for cartilage-associated protein (CRTAP), P3H1 or cyclophilin B (CYPB) cause a severe skeletal dysplasia in mice and humans that is classified as recessive osteogenesis imperfecta type VII, VIII or IX, respectively [1,2,3]
P3h3 and Sc65 were expressed at much lower levels in testis compared to P3h1 and Crtap, and overall all of them were more expressed at postnatal day 5 (P5) compared to later age groups
Summary
The Leprecan family of proteins is composed of five members that mostly localize to the endoplasmic reticulum (ER). CRTAP and P3H1 form a stable complex in the ER that includes a third component, cyclophilin B (CYPB), a prolyl cis-trans isomerase [1]. This trimeric complex, known as the prolyl 3hydroxylation complex, is essential for proper collagen modification and folding in the ER and for healthy bone formation. Mutations in the gene coding for P3H2 instead have been associated with recessive severe myopia in at least two distinct families and likely impact collagen modifications in the eye [4,5]. Leprecan genes and mutations thereof are relevant in human disease and the underlying cause appears to be primarily related to collagen alterations
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