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

Jayashree Desai, Mark E. Shannon, Mahlon Johnson, David W. Ruff, Lori A. Hughes, Marilyn K. Kerley, Donald A. Carpenter, Dabney K. Johnson, Eugene M. Rinchik, Cymbeline T. Culiat

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

The mammalian Nell1 gene encodes a protein kinase C-β1 (PKC-β1) binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Over-expression 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. 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 (ECM) 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 ECM proteins can lead to anomalies in these structures.

Original languageEnglish (US)
Pages (from-to)1329-1341
Number of pages13
JournalHuman Molecular Genetics
Volume15
Issue number8
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

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Extracellular Matrix Proteins
Osteogenesis
Genes
Spine
Spinal Curvatures
Cranial Sutures
Ethylnitrosourea
Ehlers-Danlos Syndrome
Chondrogenesis
Craniosynostoses
Nonsense Codon
Osteoblasts
Point Mutation
Skull
Codon
Protein Kinase C
Reverse Transcription
Cartilage
Cysteine
Organism Cloning

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. / Desai, Jayashree; Shannon, Mark E.; Johnson, Mahlon; Ruff, David W.; Hughes, Lori A.; Kerley, Marilyn K.; Carpenter, Donald A.; Johnson, Dabney K.; Rinchik, Eugene M.; Culiat, Cymbeline T.

In: Human Molecular Genetics, Vol. 15, No. 8, 01.04.2006, p. 1329-1341.

Research output: Contribution to journalArticle

Desai, J, Shannon, ME, Johnson, M, Ruff, DW, Hughes, LA, Kerley, MK, Carpenter, DA, Johnson, DK, Rinchik, EM & Culiat, CT 2006, 'Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects', Human Molecular Genetics, vol. 15, no. 8, pp. 1329-1341. https://doi.org/10.1093/hmg/ddl053
Desai, Jayashree ; Shannon, Mark E. ; Johnson, Mahlon ; Ruff, David W. ; Hughes, Lori A. ; Kerley, Marilyn K. ; Carpenter, Donald A. ; Johnson, Dabney K. ; Rinchik, Eugene M. ; Culiat, Cymbeline T. / Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 8. pp. 1329-1341.
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