title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
abstract: Tubulin alpha 8 (Tuba8) is the most divergent member of the highly conserved alpha tubulin family, and uniquely lacks two key post-translational modification sites. It is abundantly expressed in testis and muscle, with lower levels in the brain. We previously identified homozygous hypomorphic TUBA8 mutations in human subjects with a polymicrogyria (PMG) syndrome, suggesting its involvement in development of the cerebral cortex. We have now generated and characterized a Tuba8 knockout mouse model. Homozygous mice were confirmed to lack Tuba8 protein in the testis, but did not display PMG and appeared to be neurologically normal. In response to this finding, we re-analyzed the human PMG subjects using whole exome sequencing. This resulted in identification of an additional homozygous loss-of-function mutation in SNAP29, suggesting that SNAP29 deficiency, rather than TUBA8 deficiency, may underlie most or all of the neurodevelopmental anomalies in these subjects. Nonetheless, in the mouse brain, Tuba8 specifically localised to the cerebellar Purkinje cells, suggesting that the human mutations may affect or modify motor control. In the testis, Tuba8 localisation was cell-type specific. It was restricted to spermiogenesis with a strong acrosomal localization that was gradually replaced by cytoplasmic distribution and was absent from spermatozoa. Although the knockout mice were fertile, the localisation pattern indicated that Tuba8 may have a role in spermatid development during spermatogenesis, rather than as a component of the mature microtubule-rich flagellum itself.
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Christine P
authors.identifier: http://orcid.org/0000-0001-6861-359X
authors.initials: CP
authors.lastname: Diggle
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Martinez-Garay
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Molnar
authors.affiliation: School of Medical Sciences, University of Bradford, Bradford, United Kingdom.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Brinkworth
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Ed
authors.initials: E
authors.lastname: White
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Ewan
authors.initials: E
authors.lastname: Fowler
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Hughes
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Hayward
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Watson
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Crinnion
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Aruna
authors.initials: A
authors.lastname: Asipu
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: P Louise
authors.initials: PL
authors.lastname: Coletta
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: T Neil
authors.initials: TN
authors.lastname: Dear
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Peckham
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Ewan E
authors.initials: EE
authors.lastname: Morrison
authors.affiliation: School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology*; D059472:Exome; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D013091:Spermatogenesis / Q000235:genetics*; D014404:Tubulin / Q000235:genetics*
chemical_list: D014404:Tubulin