title: A missense mutation in the transcription factor ETV5 leads to sterility, increased embryonic and perinatal death, postnatal growth restriction, renal asymmetry and polydactyly in the mouse.
abstract: ETV5 (Ets variant gene 5) is a transcription factor that is required for fertility. In this study, we demonstrate that ETV5 plays additional roles in embryonic and postnatal developmental processes in the mouse. Through a genome-wide mouse mutagenesis approach, we generated a sterile mouse line that carried a nonsense mutation in exon 12 of the Etv5 gene. The mutation led to the conversion of lysine at position 412 into a premature termination codon (PTC) within the ETS DNA binding domain of the protein. We showed that the PTC-containing allele produced a highly unstable mRNA, which in turn resulted in an undetectable level of ETV5 protein. The Etv5 mutation resulted in male and female sterility as determined by breeding experiments. Mutant males were sterile due to a progressive loss of spermatogonia, which ultimately resulted in a Sertoli cell only phenotype by 8 week-of-age. Further, the ETV5 target genes Cxcr4 and Ccl9 were significantly down-regulated in mutant neonate testes. CXCR4 and CCL9 have been implicated in the maintenance and migration of spermatogonia, respectively. Moreover, the Etv5 mutation resulted in several developmental abnormalities including an increased incidence of embryonic and perinatal lethality, postnatal growth restriction, polydactyly and renal asymmetry. Thus, our data define a physiological role for ETV5 in many aspects of development including embryonic and perinatal survival, postnatal growth, limb patterning, kidney development and fertility.
authors.affiliation: The Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Duangporn
authors.initials: D
authors.lastname: Jamsai
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Clark
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Belinda
authors.initials: B
authors.lastname: Whittle
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
authors.forename: Moira K
authors.initials: MK
authors.lastname: O'Bryan
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007246:Infertility / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000002:abnormalities / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D017689:Polydactyly / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013091:Spermatogenesis / Q000235:genetics; D013093:Spermatogonia / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; C095218:Ccl9 protein, mouse; D019742:Chemokines, CC; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D019402:Macrophage Inflammatory Proteins; D019718:Receptors, CXCR4; D014157:Transcription Factors