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LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in
Krista A Geister1, Michelle L Brinkmeier2, Leonard Y Cheung2
1Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
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.
Insights
Genetic defects in the protein of the centriole 1a (Poc1a) gene cause skeletal dysplasia and male infertility in mice. This study identifies a LINE-1 retrotransposon insertion disrupting Poc1a, leading to cellular and developmental abnormalities.
Area of Science:
- Genetics
- Developmental Biology
- Cell Biology
Background:
- Skeletal dysplasias are a genetically diverse group of disorders causing short stature, often linked to cellular process disruptions.
- Centrosome dysfunction is implicated in various skeletal abnormalities and primordial dwarfisms.
Purpose of the Study:
- To identify the genetic cause of skeletal dysplasia and male infertility in the 'chagun' mouse mutant.
- To investigate the cellular and developmental consequences of the identified genetic defect.
Main Methods:
- Genetic sequencing to identify the causative mutation in the chagun mouse.
- Analysis of mutant fibroblast cell lines for defects in cilia formation and spindle organization.
- Spermatogonial stem cell transplantation to assess the role of Poc1a in spermatogenesis and Sertoli cell function.
- Histological examination of growth plates to evaluate chondrocyte behavior and skeletal development.
Main Results:
- The chagun mutation results from a LINE-1 retrotransposon insertion disrupting the Poc1a gene.
- Mutant fibroblasts exhibit impaired cilia formation and multipolar spindles, indicating centrosome dysfunction.
- Male mice display defective spermatogenesis, germ cell loss, and infertility.
- Spermatogonial stem cell transplantation confirms Poc1a's essential role in Sertoli and germ cell function.
- Growth plates show disorganized chondrocyte proliferation, impaired re-alignment, and increased apoptosis, leading to short stature.
Conclusions:
- Disruption of Poc1a via retrotransposon insertion is the cause of skeletal dysplasia and male infertility in the chagun mouse.
- Centrosome dysfunction, as exemplified by Poc1a deficiency, significantly impacts skeletal growth and male reproductive capacity.
- This mouse model provides insights into the role of centrosome components in skeletal development and fertility.
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