title: Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus.
abstract: The Drosophila Fused (Fu) kinase is an integral component of the Hedgehog (Hh) pathway that helps promote Hh-dependent gene transcription. Vertebrate homologues of Fu function in the Hh pathway in vitro, suggesting that Fu is evolutionarily conserved. We have generated fused (stk36) knockout mice to address the in vivo function of the mouse Fu (mFu) homologue. fused knockouts develop normally, being born in Mendelian ratios, but fail to thrive within 2 weeks, displaying profound growth retardation with communicating hydrocephalus and early mortality. The fused gene is expressed highly in ependymal cells and the choroid plexus, tissues involved in the production and circulation of cerebral spinal fluid (CSF), suggesting that loss of mFu disrupts CSF homeostasis. Similarly, fused is highly expressed in the nasal epithelium, where fused knockouts display bilateral suppurative rhinitis. No obvious defects were observed in the development of organs where Hh signaling is required (limbs, face, bones, etc.). Specification of neuronal cell fates by Hh in the neural tube was normal in fused knockouts, and induction of Hh target genes in numerous tissues is not affected by the loss of mFu. Furthermore, stimulation of fused knockout cerebellar granule cells to proliferate with Sonic Hh revealed no defect in Hh signal transmission. These results show that the mFu homologue is not required for Hh signaling during embryonic development but is required for proper postnatal development, possibly by regulating the CSF homeostasis or ciliary function.
authors.affiliation: Department of Molecular Biology, South San Francisco, CA 94080, USA. mmerch@gene.com
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.forename: Shiuh-Ming
authors.initials: SM
authors.lastname: Luoh
authors.forename: Gretchen D
authors.initials: GD
authors.lastname: Frantz
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Chalasani
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Marjie
authors.initials: M
authors.lastname: van Hoy
authors.forename: Julio
authors.initials: J
authors.lastname: Ramirez
authors.forename: Annie K
authors.initials: AK
authors.lastname: Ogasawara
authors.forename: Leanne M
authors.initials: LM
authors.lastname: McFarland
authors.forename: Ellen H
authors.initials: EH
authors.lastname: Filvaroff
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000818:Animals; D060466:Axin Protein; D019070:Cell Lineage; D049109:Cell Proliferation; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D005838:Genotype; D006579:Heterozygote; D006849:Hydrocephalus / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012220:Rhinitis / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D060466:Axin Protein; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; D001616:beta-Galactosidase