The Heterozygous Disproportionate micromelia (Dmm) Mouse: Morphological Changes in Fetal Cartilage Precede Postnatal Dwarfism and Compared to Lethal Homozygotes Can Explain the Mild Phenotype

Robert E. Seegmiller ^1*, Brandon D. Bomsta ¹, Laura C. Bridgewater ¹, Cindy M. Niederhauser ¹, Carolina Montaño ¹, Sterling Sudweeks ¹, David R. Eyre ¹ and Russell J. Fernandes ¹

¹ Departments of Physiology and Developmental Biology (RES,BDB,SS) and Microbiology and Molecular Biology (LCB,CMN,CM), Brigham Young University, Provo, Utah, and Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington (DRE,RJF)

^* To whom correspondence should be addressed. E-mail: Robert_seegmiller{at}byu.edu.

Submitted on April 17, 2008
Accepted on 15 July 2008

	Abstract

The Disproportionate micromelia (Dmm) mouse has a mutation in the C-propeptide coding region of the Col2a1 gene which causes lethal dwarfism when homozygous (Dmm/Dmm), but causes only mild dwarfism observable approximately one-week postpartum when heterozygous (Dmm/+). The purpose of the present study was two-fold: first, to analyze and quantify morphological changes that precede the expression of mild dwarfism in Dmm/+ animals, and second, to compare morphological alterations between Dmm/+ and Dmm/Dmm fetal cartilage that may correlate with the marked skeletal differences between mild and lethal dwarfism. Light and electron-transmission microscopy were used to visualize structure of chondrocytes and extracellular matrix (ECM) of fetal rib cartilage. Both Dmm/+ and Dmm/Dmm fetal rib cartilage had significantly larger chondrocytes, greater cell density, and less ECM per unit area than +/+ littermates. Quantitative RT-PCR revealed a decrease in aggrecan mRNA in Dmm/+ versus +/+ cartilage. Furthermore, the cytoplasm of chondrocytes in Dmm/+ and Dmm/Dmm cartilage was occupied by significantly more distended rough endoplasmic reticulum (RER) when compared with wild-type chondrocytes. Fibril diameters and packing densities of +/+ and Dmm/+ cartilage were similar, but Dmm/Dmm cartilage showed thinner, sparsely distributed fibrils. These findings support the prevailing hypothesis that a C-propeptide mutation could interrupt the normal assembly and secretion of type II procollagen trimers, resulting in a buildup of pro1(II) chains in the RER and a reduced rate of matrix synthesis. Thus, intracellular entrapment of pro1(II) appears to be primarily responsible for the dominant-negative effect of the Dmm mutation in the expression of dwarfism.

Key Words: chondrodysplasia, extracellular matrix, Disproportionate micromelia (Dmm), Col2a1, C-propeptide

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