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Molecular and Cellular Biology, April 2006, p. 2511-2518, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2511-2518.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hydrops Fetalis, Cardiovascular Defects, and Embryonic Lethality in Mice Lacking the Calcitonin Receptor-Like Receptor Gene

Ryan T. Dackor,1,3 Kimberly Fritz-Six,1 William P. Dunworth,1,3 Carrie L. Gibbons,1 Oliver Smithies,2 and Kathleen M. Caron1*

Department of Cell & Molecular Physiology,1 Department of Pathology and Laboratory Medicine,2 Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275993

Received 30 August 2005/ Returned for modification 19 September 2005/ Accepted 3 January 2006

Adrenomedullin (AM) is a multifunctional peptide vasodilator that is essential for life. To date, numerous in vitro studies have suggested that AM can mediate its biological effects through at least three different receptors. To determine the in vivo importance of the most likely candidate receptor, calcitonin receptor-like receptor, a gene-targeted knockout model of the gene was generated. Mice heterozygous for the targeted Calcrl allele appear normal, survive to adulthood, and reproduce. However, heterozygote matings fail to produce viable Calcrl–/– pups, demonstrating that Calcrl is essential for survival. Timed matings confirmed that Calcrl–/– embryos die between embryonic day 13.5 (E13.5) and E14.5 of gestation. The Calcrl–/– embryos exhibit extreme hydrops fetalis and cardiovascular defects, including thin vascular smooth muscle walls and small, disorganized hearts remarkably similar to the previously characterized AM–/– phenotype. In vivo assays of cellular proliferation and apoptosis in the hearts and vasculature of Calcrl–/– and AM–/– embryos support the concept that AM signaling is a crucial mediator of cardiovascular development. The Calcrl gene targeted mice provide the first in vivo genetic evidence that CLR functions as an AM receptor during embryonic development.

* Corresponding author. Mailing address: Department of Cell & Molecular Physiology, CB #7545, 6330 MBRB, 103 Mason Farm Rd., The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-5215. Fax: (919) 966-5230. E-mail: kathleen_caron{at}med.unc.edu.

Molecular and Cellular Biology, April 2006, p. 2511-2518, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2511-2518.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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