Unintended targeting of <i>Dmp1-Cre</i> reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice.

Abstract

Cre/loxP technology has been widely used to study cell type-specific functions of genes. Proper interpretation of such data critically depends on a clear understanding of the tissue specificity of Cre expression. The <i>Dmp1-Cre</i> mouse, expressing Cre from a 14-kb DNA fragment of the mouse <i>Dmp1</i> gene, has become a common tool for studying gene function in osteocytes, but the presumed cell specificity is yet to be fully established. By using the <i>Ai9</i> reporter line that expresses a red fluorescent protein upon Cre recombination, we find that in 2-month-old mice, <i>Dmp1-Cre</i> targets not only osteocytes within the bone matrix but also osteoblasts on the bone surface and preosteoblasts at the metaphyseal chondro-osseous junction. In the bone marrow, Cre activity is evident in certain stromal cells adjacent to the blood vessels, but not in adipocytes. Outside the skeleton, <i>Dmp1-Cre</i> marks not only the skeletal muscle fibers, certain cells in the cerebellum and the hindbrain but also gastric and intestinal mesenchymal cells that express <i>Pdgfra</i>. Confirming the utility of <i>Dmp1-Cre</i> in the gastrointestinal mesenchyme, deletion of <i>Bmpr1a</i> with <i>Dmp1-Cre</i> causes numerous large polyps along the gastrointestinal tract, consistent with prior work involving inhibition of BMP signaling. Thus, caution needs to be exercised when using <i>Dmp1-Cre</i> because it targets not only the osteoblast lineage at an earlier stage than previously appreciated, but also a number of non-skeletal cell types.