Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus.
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.
Merchant
Mark
M
Department of Molecular Biology, South San Francisco, CA 94080, USA. mmerch@gene.com
Evangelista
Marie
M
Luoh
Shiuh-Ming
SM
Frantz
Gretchen D
GD
Chalasani
Sreedevi
S
Carano
Richard A D
RA
van Hoy
Marjie
M
Ramirez
Julio
J
Ogasawara
Annie K
AK
McFarland
Leanne M
LM
Filvaroff
Ellen H
EH
French
Dorothy M
DM
de Sauvage
Frederic J
FJ
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
D060466:Axin Protein; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; D001616:beta-Galactosidase