LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice.
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.
Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Krista A
KA
Geister
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Michelle L
ML
Brinkmeier
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Leonard Y
LY
Cheung
Roche NimbleGen, Inc., Research and Development, Madison, Wisconsin, United States of America.
Jennifer
J
Wendt
School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, Washington, United States of America.
Melissa J
MJ
Oatley
Roche NimbleGen, Inc., Research and Development, Madison, Wisconsin, United States of America.
Daniel L
DL
Burgess
Department of Orthopedic Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
Kenneth M
KM
Kozloff
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
James D
JD
Cavalcoli
School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, Washington, United States of America.
Jon M
JM
Oatley
Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, United States of America; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Sally A
SA
Camper
D000818:Animals; D018797:Cell Cycle Proteins; D002502:Centrioles / Q000235:genetics; D018385:Centrosome / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013093:Spermatogonia / Q000378:metabolism
C534000:CENPW protein, human; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C575745:POC1A protein, human; C000607991:Poc1a protein, mouse; D011506:Proteins