Human Molecular Genetics Advance Access originally published online on June 18, 2008
Human Molecular Genetics 2008 17(18):2803-2818; doi:10.1093/hmg/ddn179
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Haploinsufficiency of the germ cell-specific nuclear RNA binding protein hnRNP G-T prevents functional spermatogenesis in the mouse
1 Institute of Human Genetics, Newcastle University, Central Parkway, Newcastle NE1 3BZ, UK 2 Department of Public Health and Cell Biology, Section of Anatomy, University of Rome ‘Tor Vergata’, Rome, Italy 3 IRCSS Fondazione Santa Lucia, Rome, Italy 4 MRC Reproductive Sciences Unit, Centre for Reproductive Biology, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland, UK 5 Génétique moléculaire de la spermatogenèse, Inserm U491, Faculté de médecine, 27, bd Jean Moulin 13385, Marseille, France 6 Institut fur Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universitat Erlangen-Nurnberg, Fahrstrasse 17 91054, Erlangen, Germany 7 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 741 South Limestone, Lexington, KY 40536-0509, USA 8 North East Stem Cell Institute (NESCI), Newcastle, UK
* To whom correspondence should be addressed. Tel: +1 912418694; Fax: +1 912418666; Email: david.elliott{at}ncl.ac.uk
Received May 1, 2008; Revised May 29, 2008; Accepted June 16, 2008
Human HNRNPGT, encoding the protein hnRNP G-T, is one of several autosomal retrogenes derived from RBMX. It has been suggested that HNRNPGT functionally replaces the sex-linked RBMX and RBMY genes during male meiosis. We show here that during normal mouse germ cell development, hnRNP G-T protein is strongly expressed during and after meiosis when proteins expressed from Rbmx or Rbmx-like genes are absent. Amongst these Rbmx-like genes, DNA sequence analyses indicate that two other mouse autosomal Rbmx-derived retrogenes have evolved recently in rodents and one already shows signs of degenerating into a non-expressed pseudogene. In contrast, orthologues of Hnrnpgt are present in all four major groups of placental mammals. The sequence of Hnrnpgt is under considerable positive selection suggesting it performs an important germ cell function in eutherians. To test this, we inactivated Hnrnpgt in ES cells and studied its function during spermatogenesis in chimaeric mice. Although germ cells heterozygous for this targeted allele could produce sperm, they did not contribute to the next generation. Chimaeric mice with a high level of mutant germ cells were infertile with low sperm counts and a high frequency of degenerate seminiferous tubules and abnormal sperm. Chimaeras made from a 1:1 mix of targeted and wild-type ES cell clones transmitted wild-type germ cells only. Our data show that haploinsufficiency of Hnrnpgt results in abnormal sperm production in the mouse. Genetic defects resulting in reduced levels of HNRNPGT could, therefore, be a cause of male infertility in humans.
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