Impaired Abdominal Wall Development and Deficient Wound Healing in Mice Lacking Aortic Carboxypeptidase-Like Protein

Abstract

Aortic carboxypeptidase-like protein (ACLP) is a member of a diverse group of proteins that contain a domain with similarity to that of the Dictyostelium discoideum protein discoidin I. The discoidin domain has been identified in mammalian milk fat globule membrane proteins, blood coagulation factors, and receptor tyrosine kinases, where it may facilitate cell aggregation, adhesion, or cell-cell recognition. Here we show that ACLP is a secreted protein that associates with the extracellular matrix (ECM). During mouse embryogenesis, ACLP is abundantly expressed in the ECM of collagen-rich tissues, including the vasculature, dermis, and the developing skeleton. We deleted the ACLP gene in mice by homologous recombination. The majority of ACLP^−/− mice die perinatally due to gastroschisis, a severe disruption of the anterior abdominal wall and herniation of the abdominal organs. ACLP^−/− mice that survived to adulthood developed nonhealing skin wounds. Following injury by a dermal punch biopsy, ACLP^−/− mice exhibited deficient wound healing compared with controls. In addition, dermal fibroblasts isolated from ACLP^−/− 18.5-day-postconception embryos exhibited a reduced proliferative capacity compared with wild-type cells. These results indicate that ACLP is an ECM protein that is essential for embryonic development and dermal wound healing processes.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grants HL10113 (M.D.L.) and HL57977 (M.-E.L. and S.-F.Y.) and a grant from the March of Dimes Birth Defects Foundation (M.-E.L. and M.A.P.).

We thank Bonna Ith for expert technical assistance.