Neonatal Respiratory Failure with Retarded Perinatal Lung Maturation in Mice Caused by Reticulocalbin 3 Disruption

Abstract

Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum lumen protein localized to the secretory pathway. As a Ca2t-binding protein of 45 kDa (Cab45)/Rcn/ER Ca2t-binding protein of 55 kDa (ERC45)/calumenin (CREC) family member, Rcn3 is reported to function as a chaperone protein involved in protein synthesis and secretion; however, the biological role of Rcn3 is largely unknown. The results presented here, for the first time, depict an indispensable physiological role of Rcn3 in perinatal lung maturation by using an Rcn3 gene knockout mouse model. These mutant mice die immediately at birth owing to atelectasis-induced neonatal respiratory distress, although these embryos are produced with grossly normal development. This respiratory distress results from a failure of functional maturation of alveolar epithelial type II cells during alveogenesis. This immaturity of type II cells is associated with a dramatic reduction in surfactant protein A and D, a disruption in surfactant phospholipid homeostasis, and a disorder in lamellar body. In vitro studies further show that Rcn3 deficiency blunts the secretion of surfactant proteins and phospholipids from lung epithelial cells, suggesting a decrease in availability of surfactants for their surface activity. Collectively, these observations indicate an essential role of Rcn3 in perinatal lung maturation and neonatal respiratory adaptation as well as shed additional light on the mechanism of neonatal respiratory distress syndrome development.

Suppression of Rcn3 in the alveolar epithelial cells may have beneficial effect against COPD

“…Consistently, high expression of Rcn3 in human lung tissue has also been reported by Hou Yu et al [8]. We further revealed that Rcn3 knockout mice died from neonatal respiratory distress due to the impaired maturation of alveolar epithelial type II cells (AECIIs), suggesting its potential role in regulating AECIIs function [7]. In addition, we demonstrated that the selective deletion of Rcn3 in AECIIs exacerbated bleomycin-induced lung fibrosis [9].…”

“…It belongs to the Cab45/Rcn/ERC45/Calumenin family [6], the biological function of which is still far from clear. We have previously reported that Rcn3 was expressed in a variety of mouse tissues with the highest expression in the lung [7]. Consistently, high expression of Rcn3 in human lung tissue has also been reported by Hou Yu et al [8].…”

“…Previous study has found that mice with whole body Rcn3 knockout died after birth because of respiratory failure [7]. To further investigate the role of Rcn3 in pulmonary diseases, selective Rcn3 knockout in AECIIs were successfully established in our laboratory, and have been employed to study the function of Rcn3 in the development of lung fibrosis [9].…”

Reticulocalbin 3 is Involved in Postnatal Tendon Development by Regulating Collagen Fibrillogenesis and Cellular Maturation

“…Moreover, Rcn3 emerged as a new potential regulator of collagen production in vitro 27 . Rcn3 knockout mice exhibited neonatal lethality caused by impaired synthesis and secretion of surfactant in lung tissue 28 . However, the function of Rnc3 in postnatal tendon development is not known.…”

Knockout of microRNA‑26a promotes lung development and pulmonary surfactant synthesis

“…PS is a complex lipid and protein mixture, produced by AECIIs from late fetal development onwards, and prevents alveolar collapse by regulating surface tension at the pulmonary air-liquid interface (4). It is composed of 90% lipids and 10% surfactant-associated proteins, including surfactant protein (SP)-A, SP-B, SP-C and SP-D. SP-A and SP-D, hydrophilic collectin proteins, participate in pulmonary host defense and modify immune responses, whereas SP-B and SP-C, small hydrophobic proteins, together with dipalmitoylphosphatidylcholine (DPPC), confer surface tension lowering properties to the material (5)(6)(7). MicroRNAs (miRNAs/miRs) are a class of small non-coding RNAs that suppress gene translation, most commonly through promoting mRNA degradation or disrupting mRNA translation.…”