title: Hydrocephalus, situs inversus, chronic sinusitis, and male infertility in DNA polymerase lambda-deficient mice: possible implication for the pathogenesis of immotile cilia syndrome.
abstract: A growing number of DNA polymerases have been identified, although their physiological function and relation to human disease remain mostly unknown. DNA polymerase lambda (Pol lambda; also known as Pol beta2) has recently been identified as a member of the X family of DNA polymerases and shares 32% amino acid sequence identity with DNA Pol beta within the polymerase domain. With the use of homologous recombination, we generated Pol lambda(-/-) mice. Pol lambda(-/-) mice develop hydrocephalus with marked dilation of the lateral ventricles and exhibit a high rate of mortality after birth, although embryonic development appears normal. Pol lambda(-/-) mice also show situs inversus totalis and chronic suppurative sinusitis. The surviving male, but not female, Pol lambda(-/-) mice are sterile as a result of spermatozoal immobility. Microinjection of sperm from male Pol lambda(-/-) mice into oocytes gives rise to normal offspring, suggesting that the meiotic process is not impaired. Ultrastructural analysis reveals that inner dynein arms of cilia from both the ependymal cell layer and respiratory epithelium are defective, which may underlie the pathogenesis of hydrocephalus, situs inversus totalis, chronic sinusitis, and male infertility. Sensitivity of Pol lambda(-/-) cells to various kinds of DNA damage is indistinguishable from that of Pol lambda(+/+) cells. Collectively, Pol lambda(-/-) mice may provide a useful model for clarifying the pathogenesis of immotile cilia syndrome.
authors.affiliation: Department of Geriatric Research, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Miho
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takai
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagashima
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
mesh_terms: D000818:Animals; D002908:Chronic Disease; D002925:Ciliary Motility Disorders / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D019951:DNA Polymerase beta / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006849:Hydrocephalus / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D007248:Infertility, Male / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D012852:Sinusitis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D012857:Situs Inversus / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020554:Sperm Injections, Intracytoplasmic
chemical_list: C415367:DNA polymerase beta2; D019951:DNA Polymerase beta