RESUMO
Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.
Assuntos
Adenosina Trifosfatases/fisiologia , Centríolos/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Cílios/fisiologia , Adenosina Trifosfatases/genética , Animais , Estudos de Casos e Controles , Proliferação de Células/genética , Proliferação de Células/fisiologia , Centríolos/genética , Córtex Cerebral/anormalidades , Córtex Cerebral/metabolismo , Cílios/genética , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Fibroblastos/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Katanina , Camundongos , Microcefalia/genética , Mutação , Linhagem , Splicing de RNA/genética , População Branca/genética , Peixe-ZebraRESUMO
The Singapore Stem Cell Bank has generated human embryonic stem cell banks from clinical-grade cell lines ESI-017, ESI-035, ESI-049, and ESI-053. All banks were prepared and characterized according to principles of Good Laboratory Practice for quality assurance. Importantly, each cell line has clearly documented and approved ethical provenance and meets recognized standards for performance and safety. The banks are intended to facilitate the translation of stem cell research to clinical medicine by enabling early phase research and development with high-quality, low-cost cells that are also available as clinical-grade stocks.