Regulation of mouse lung development by the extracellular calcium‐sensing receptor, CaR

Abstract

Postnatal lung function is critically dependent upon optimal embryonic lung development. As the free ionized plasma calcium concentration ( 2+o , acting through a developmentally regulated CaR, is an important extrinsic factor that modulates the intrinsic lung developmental programme. Our observations support a novel role for the CaR in preventing hyperplastic lung disease in utero.

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Recent reports clearly point to a role for the CaSR as a regulator of early development and as a guardian of the homeostatic balance between proliferation and differentiation in adults [19,68,70,71,73,75,89,92]. The identification of CaSR mutations that cause FHH and hypocalcemia [93][94][95][96][97][98], and the recent discoveries implicating the dysregulation of CaSR signaling in many other diseases [99,[113][114][115][119][120][121][122][123][124], position the CaSR as a broad therapeutic target.…”

“…In addition, the CaSR plays a crucial role in the elaboration of normal dendritic arbors in pyramidal neurons during early postnatal development of the mouse hippocampus [70]. Regarding the developing mouse lung, Finney and colleagues demonstrated that, between embryonic days 10.5 and 16.5, calcium concentrations similar to those encountered in developing fetuses (~1.7 mM) inhibit lung branching morphogenesis and cellular proliferation while promoting lung fluid secretion via activation of the CaSR [71]. After embryonic day 16.5, CaSR expression progressively diminishes and is absent in adult lung tissue [1,71,72].…”

“…Regarding the developing mouse lung, Finney and colleagues demonstrated that, between embryonic days 10.5 and 16.5, calcium concentrations similar to those encountered in developing fetuses (~1.7 mM) inhibit lung branching morphogenesis and cellular proliferation while promoting lung fluid secretion via activation of the CaSR [71]. After embryonic day 16.5, CaSR expression progressively diminishes and is absent in adult lung tissue [1,71,72]. By means of tissuespecific deletion of the CaSR, it was evidenced that CaSR expression is crucial for the proper fetal bone development and mineralization [73].…”

Functional expression of the multimodal extracellular calcium-sensing receptor in pulmonary neuroendocrine cells

“…In developing mouse lungs, CaSR mRNA and protein is present in airway epithelium within a narrow developmental window, between embryonic day (ED) 11.5 and ED16.5, regulating lung branching morphogenesis. After ED16.5, CaSR expression progressively decreases and has so far not been detected in postnatal lung tissue (Finney et al, 2008;Riccardi et al, 2009). However, mRNA expression of CaSR in postnatal lungs was studied in whole-lung tissue blocks only, without the ability of precise localization of potential mRNA expression at the level of less-abundant cell types.…”

Allosteric Modulation of the Calcium-sensing Receptor by γ-Glutamyl Peptides

“…5, 6), modulates synaptic transmission (7) and cellular differentiation in mesenchymal tissues (4), as well as engraftment of stem cells in specific niches (8), and organogenesis e.g. in the lung (9) and central nervous system (10,11). Accompanying this remarkable plasticity, the CaR, like several other class C GPCRs, binds multiple physiologically relevant ligands to control intracellular signaling pathways (Reviews: Refs.…”