Research Resource: Haploinsufficiency of Receptor Activity-Modifying Protein-2 (Ramp2) Causes Reduced Fertility, Hyperprolactinemia, Skeletal Abnormalities, and Endocrine Dysfunction in Mice

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 25; no. 7; pp. 1244 - 1253
• Main Authors: Kadmiel, Mahita, Fritz-Six, Kimberly, Pacharne, Suruchi, Richards, Gareth O, Li, Manyu, Skerry, Tim M, Caron, Kathleen M
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.07.2011; Oxford University Press
• Subjects: Animals; Animals, Newborn; Bone and Bones - abnormalities; Bone and Bones - diagnostic imaging; Bone Density; Bone Development; Female; Femur - abnormalities; Femur - diagnostic imaging; Fetal Death - genetics; Genes, Lethal; Haploinsufficiency; Hyperplasia; Hyperprolactinemia - genetics; Infertility, Female - genetics; Lumbar Vertebrae - abnormalities; Lumbar Vertebrae - diagnostic imaging; Male; Mammary Glands, Animal - abnormalities; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Pituitary Gland - pathology; Pregnancy; Radiography; Receptor Activity-Modifying Protein 2 - genetics; Research Resource; Tibia - abnormalities; Tibia - diagnostic imaging
• DOI: 10.1210/me.2010-0400
• ISSN: 0888-8809

Receptor activity-modifying protein-2 (RAMP2) is a single-pass transmembrane protein that can regulate the trafficking, ligand binding, and signaling of several G protein-coupled receptors (GPCR). The most well-characterized role of RAMP2 is in the regulation of adrenomedullin (AM) binding to calcitonin receptor-like receptor (CLR), and our previous studies using knockout mouse models support this canonical signaling paradigm. For example, Ramp2−/− mice die at midgestation with a precise phenocopy of the AM−/− and Calcrl−/− mice. In contrast, Ramp2+/− mice are viable and exhibit an expanded variety of phenotypes that are distinct from those of Calcrl+/− mice. Using Ramp2+/− female mice, we demonstrate that a modest decrease in Ramp2 expression causes severe reproductive defects characterized by fetal growth restriction, fetal demise, and postnatal lethality that is independent of the genotype and gender of the offspring. Ramp2+/− female mice also exhibit hyperprolactinemia during pregnancy and in basal conditions. Consistent with hyperprolactinemia, Ramp2+/− female mice have enlarged pituitary glands, accelerated mammary gland development, and skeletal abnormalities including delayed bone development and decreased bone mineral density. Because RAMP2 has been shown to associate with numerous GPCR, it is likely that signaling of one or more of these GPCR is compromised in Ramp2+/− mice, yet the precise identification of these receptors remains to be elucidated. Taken together, this work reveals an essential role for RAMP2 in endocrine physiology and provides the first in vivo evidence for a physiological role of RAMP2 beyond that of AM/CLR signaling.