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Human Molecular Genetics Advance Access published online on March 14, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl053
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 4, 2006
Revised March 7, 2006
Accepted March 7, 2006

Article

Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects

Jayashree Desai 1, Mark E. Shannon 2, Mahlon D. Johnson 3, David W. Ruff 2, Lori A. Hughes 4, Marilyn K. Kerley 4, Donald A. Carpenter 4, Dabney K. Johnson 4, Eugene M. Rinchik 5, and Cymbeline T. Culiat 6 *

1 Graduate School for Genome Science and Technology, University of Tennessee-Oak Ridge National Laboratory, 1060 Commerce Park, Oak Ridge, TN 37831, USA
2 Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404, USA
3 The University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920-6999, USA
4 Life Sciences Division, Oak Ridge National Laboratory, P.O. Box 2008, Oak Ridge, TN 37831-6445, USA
5 Life Sciences Division, Oak Ridge National Laboratory, P.O. Box 2008, Oak Ridge, TN 37831-6445, USA; Department of Biochemistry, Cellular and Molecular Biology, The University of Tennessee, Knoxville, TN 37996, USA; Present address: Taconic, One Hudson City Centre, Hudson, New York 12534, USA
6 Life Sciences Division, Oak Ridge National Laboratory, P.O. Box 2008, Bethel Valley Road, Oak Ridge, TN 37831-6445, USA

* To whom correspondence should be addressed.
Cymbeline T. Culiat, E-mail: culiatct{at}ornl.gov


  Abstract
The mammalian Nell1 gene encodes a protein kinase C-{beta}1 (PKC-{beta}1) binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Overexpression of Nell1 in the developing cranial sutures in both human and mouse induces craniosynostosis, the premature fusion of the growing cranial bone fronts. Here we report the generation, positional cloning and characterization of Nell16R, a recessive, neonatal-lethal point mutation in the mouse Nell1 gene, induced by N-ethyl-N-nitrosourea (ENU). Nell16R has a T -> A base change that converts a codon for cysteine into a premature stop codon [Cys(502)Ter], resulting in severe truncation of the predicted protein product and marked reduction in steady state levels of the transcript. In addition to the expected alteration of cranial morphology, Nell16R mutants manifest skeletal defects in the vertebral column and ribcage, revealing a hitherto undefined role for Nell1 in signal transduction in endochondral ossification. Real-time quantitative reverse transcription PCR assays of 219 genes showed an association between the loss of Nell1 function and reduced expression of genes for extracellular matrix proteins critical for chondrogenesis and osteogenesis. Several affected genes are involved in the human cartilage disorder Ehlers-Danlos Syndrome and other disorders associated with spinal curvature anomalies. Nell16R mutant mice are a new tool for elucidating basic mechanisms in osteoblast and chrondrocyte differentiation in the developing skull and vertebral column and understanding how perturbations in the production of extracellular matrix proteins can lead to anomalies in these structures.
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