An exon 5-less splice variant of the extracellular calcium-sensing receptor rescues absence of the full-length receptor in the developing mouse lung

ABSTRACT

The authors have recently demonstrated that, in the developing mouse lung, fetal plasma Ca²⁺ suppresses branching morphogenesis and cell proliferation while promoting fluid secretion via activation of the extracellular Ca²⁺-sensing receptor (CaSR). The aim of the current study was to further elucidate the role of Ca²⁺ in lung development by studying the effects of extracellular Ca²⁺ on fetal lung development in mice lacking the CaSR. These mice were produced by exon 5 deletion in the CaSR gene. Since such a maneuver has been known to induce the expression of an exon 5-less splice variant of the CaSR in some tissues, the molecular and functional expression of this splice variant in the developing mouse lung was also investigated. Whereas there was a mild in vivo phenotype observed in these mice, in vitro sensitivity of Casr^−/− lung explants to specific activators of the CaSR was unaffected. These results imply that compensatory expression of an exon 5-less splice variant rescues CaSR function in this mouse model and therefore a lung-specific, complete CaSR knockout model must be developed to fully appreciate the role for this receptor in lung development and the contribution of its ablation to postnatal respiratory disease.

KEYWORDS :

• branching morphogenesis
• exon 5-less splice variant
• extracellular calcium-sensing receptor
• lung development