LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice

Abstract

Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility.

FGF4retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs

“…A survey of retrogenes in the canine reference genome reported ~70 functional retrogenes in the dog; however, only the previous CFA18 FGF4 retrogene insertion has been reported to be associated with a disease causing phenotype 26,45 . Similarly in humans, the formation of processed pseudogenes in general, as well as those that retain their intended function and cause disease, is rare [46][47][48][49][50][51] .…”

Retrotransposons Manipulating Mammalian Skeletal Development in Chondrocytes

“…Subsequent genetic investigation identified the gene responsible for this chagun phenotype [20]-the Poc1a encoding protein of centriole 1A. As the name implies, this protein is a component of centrosome, suggesting its potential function in microtubule organization.…”

“…These findings indicate that ORF2 protein reverse transcribed and inserted the Cenpw cDNA into the Poc1a locus in chagun mice. Several human pedigrees harbor mutations in POC1A loci, commonly characterized by growth insufficiency [20,21]. Therefore, the chagun mice phenocopying human cases can be a good model for medical investigation of these relevant human syndromes.…”

Cep55 overexpression causes male‐specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling

“…The slides were mounted and imaged with Vectashield (Vector Laboratories, Burlingame, CA, USA) before analysis with the Invert LSM780 confocal microscope (Zeiss, Jena Germany) at Monash University's Micro Imaging facility. Specificity of the primary antibodies is as follows: Plzf 1:100 (goat, AF2944; R&D Systems) (49); Ki67 1:500 (rabbit, NCL-ki67p; Novacastra); Foxo1 1:500 (rabbit, 2880; Cell Signaling Technology) (11); anti-c-kit 1:250 (goat, AF1356; R&D Systems) (50); mouse vasa homolog (Mvh) 1:600 (mouse, ab27591; Abcam, Cambridge, United Kingdom) (51), and sex determining region Y-box (Sox)_9 1:200 (rabbit, AB5535; MilliporeSigma) (52). DAPI was used as a nuclear stain (D9564; MilliporeSigma).…”