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Molecular and Cellular Biology, August 2005, p. 7054-7068, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7054-7068.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Loss of the Serine/Threonine Kinase Fused Results in Postnatal Growth Defects and Lethality Due to Progressive Hydrocephalus

Mark Merchant,1 Marie Evangelista,1 Shiuh-Ming Luoh,2 Gretchen D. Frantz,3 Sreedevi Chalasani,3 Richard A. D. Carano,4 Marjie van Hoy,3 Julio Ramirez,3 Annie K. Ogasawara,4 Leanne M. McFarland,4 Ellen H. Filvaroff,5 Dorothy M. French,3 and Frederic J. de Sauvage1*

Departments of Molecular Biology,1 Bioinformatics,2 Pathology,3 Biomedical Imaging,4 Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 940805

Received 3 February 2005/ Returned for modification 10 April 2005/ Accepted 17 May 2005

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.

* Corresponding author. Mailing address: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: (650) 225-7044. Fax: (650) 225-6240. E-mail: mmerch{at}gene.com.

Molecular and Cellular Biology, August 2005, p. 7054-7068, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7054-7068.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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