Loss of the Serine/Threonine Kinase Fused Results in Postnatal Growth Defects and Lethality Due to Progressive Hydrocephalus
| Autor: | Mark Merchant, Julio Ramirez, Marie Evangelista, Frederic J. de Sauvage, Gretchen Frantz, Ellen Filvaroff, Leanne McFarland, Sreedevi Chalasani, Dorothy French, Richard A.D. Carano, Annie Ogasawara, Shiuh-Ming Luoh, Marjie van Hoy |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Heterozygote
Time Factors Genotype Transcription Genetic Biology Protein Serine-Threonine Kinases Mice Axin Protein Genes Reporter medicine Mammalian Genetic Models with Minimal or Complex Phenotypes Animals Cell Lineage Tissue Distribution RNA Small Interfering Molecular Biology Hedgehog Gene knockout In Situ Hybridization Cell Proliferation Cerebrospinal Fluid Rhinitis Regulation of gene expression Serine/threonine-specific protein kinase Mice Knockout Dose-Response Relationship Drug Models Genetic Reverse Transcriptase Polymerase Chain Reaction Neural tube Gene Expression Regulation Developmental Cell Biology beta-Galactosidase Molecular biology Magnetic Resonance Imaging Mice Inbred C57BL Repressor Proteins medicine.anatomical_structure Microscopy Fluorescence Knockout mouse Choroid plexus Signal transduction Hydrocephalus Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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