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Updated: Aug 10, 2026
Murine Fetal Echocardiography
Published on: February 15, 2013
Hydrops fetalis, cardiovascular defects, and embryonic lethality in mice lacking the calcitonin receptor-like
Ryan T Dackor1, Kimberly Fritz-Six, William P Dunworth
1Department of Cell & Molecular Physiology, CB #7545, 6330 MBRB, 103 Mason Farm Rd., The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
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.
Insights
Calcitonin receptor-like receptor (Calcrl) is essential for embryonic survival, with Calcrl knockout mice showing severe cardiovascular defects and embryonic lethality. This study confirms calcitonin receptor-like receptor acts as a key adrenomedullin receptor in vivo.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- Adrenomedullin (AM) is a vital peptide vasodilator with multiple biological roles.
- In vitro studies suggest AM acts via several receptors, with calcitonin receptor-like receptor (CLR) being a primary candidate.
- The in vivo function of CLR as an AM receptor remains to be fully elucidated.
Purpose of the Study:
- To investigate the in vivo role of calcitonin receptor-like receptor (CLR) in embryonic development.
- To determine if CLR is essential for mediating Adrenomedullin (AM) signaling during embryogenesis.
- To generate and characterize a gene-targeted knockout model for Calcrl.
Main Methods:
- Generation of a gene-targeted knockout mouse model for the Calcrl gene.
- Analysis of Calcrl heterozygous and homozygous mutant mice.
- Timed matings to determine embryonic lethality and developmental stages.
- Phenotypic analysis of Calcrl-/- embryos, including cardiovascular morphology.
- In vivo assays for cellular proliferation and apoptosis in embryonic tissues.
Main Results:
- Calcrl heterozygous mice are viable and fertile.
- Calcrl-/- embryos exhibit embryonic lethality between E13.5 and E14.5.
- Calcrl-/- embryos display severe hydrops fetalis and cardiovascular abnormalities, including thin vascular walls and disorganized hearts.
- These defects mirror the previously observed phenotype of Adrenomedullin knockout (AM-/-) embryos.
- Reduced cellular proliferation and increased apoptosis were noted in the cardiovascular system of Calcrl-/- embryos.
Conclusions:
- The Calcrl gene is essential for embryonic survival.
- The observed cardiovascular defects in Calcrl-/- embryos strongly implicate CLR in AM signaling during development.
- This study provides the first in vivo genetic evidence that CLR functions as a critical Adrenomedullin receptor during embryonic development.
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