Affiliation:
1. Department of Cell & Molecular Physiology
2. Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
3. Department of Pathology and Laboratory Medicine
Abstract
ABSTRACT
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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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