Neuregulin Receptor ErbB4 Functions as a Transcriptional Cofactor for the Expression of Surfactant Protein B in the Fetal Lung

Abstract

Sufficient pulmonary surfactant production is required for the fetalneonatal transition, especially in preterm infants. Neuregulin (NRG) and its transmembrane receptor ErbB4 positively regulate the onset of fetal surfactant synthesis. Details of this signaling process remain to be elucidated. ErbB4 is known to regulate gene expression in the mammary gland, where the receptor associates with the signal transducer and activator of transcription Stat5a to transactivate the b-casein gene promoter. We hypothesized that in the fetal lung, ErbB4 functions as a transcriptional regulator for surfactant protein B (Sftpb), the most critical surfactant protein gene. Re-expressing fulllength ErbB4 in primary fetal ErbB4-depleted Type II epithelial cells led to an increased expression of Sftpb mRNA. This stimulatory effect required the nuclear translocation of ErbB4 and association with Stat5a, with the resultant binding to and activation of the Sftpb promoter. We conclude that ErbB4 directly regulates important aspects of fetal lung maturation that help prepare for the fetalneonatal transition.Keywords: Surfactant; Type II cell; Stat5a; lung developmentThe differentiation of the neuronal (1, 2) and mammary (3) systems requires proper signaling between the growth factor neuregulin (NRG) and its cell-surface receptor, ErbB4. In the fetal lung, NRG is required for the initiation of fetal surfactant synthesis (4), and ErbB receptors (named because of their homology to the erythroblastoma viral gene product, v-erbB), also known as human epidermal growth factor receptors (HERs), are involved in the timely progression of fetal lung cell differentiation (4-6).Surface-active agents (surfactants) prevent pulmonary alveoli from collapsing at end-expiration. Therefore, the synthesis of surfactants by fetal pulmonary Type II cells is a crucial part of prenatal lung development (7), in preparation for the transition at birth from the intrauterine (aquatic) to the extrauterine (aerobic) environment. ErbB4, the signaling receptor for NRG, is the most prominent receptor dimerization partner in fetal Type II epithelial cells (8) and the down-regulation of ErbB4 inhibits fetal surfactant synthesis (9).Fetal ErbB4 transgenic mice that are rescued from their lethal heart defect by expressing human ErbB4 cDNA under the control of the cardiac-specific myosin heavy chain (a-HMC) promoter (HER4 heart ) (3) exhibit changes in lung function and structure, resulting in a hyperreactive airway system and alveolar simplification in adult HER4 heart (2/2) animals (10). In the fetal lung, the deletion of pulmonary ErbB4 leads to an overall delayed progression of structural and functional lung development, including the delayed expression of surfactant protein B (Sftpb). This delay is most prominent at the transition from the canalicular to the saccular stage on Embryonic Day 17. Delayed saccular development, with an increased mesenchymal area around the airspaces and a delayed onset of surfactant synthesis and Sftpb expression in HER4 heart (2/2) lungs, con...

Receptor Tyrosine Kinases in the Nucleus

“…Interestingly, there is a genetic correlation between ErbB-4 and schizophrenia (Pan et al 2011) and the involvement of the ICD fragment in controlling gene expression in relevant cell types has been reported (Wong and Weickert 2009;Allison et al 2011). Also, the maturation of fetal lung cells is reported to be dependent on secretase processing of ErbB-4 and ICD association with the transcription factors YAP (Hoeing et al 2011), STAT 5a (Zscheppang et al 2011a), and ERb (Zscheppang et al 2011b). It is suggested that these interactions allow ErbB-4 to regulate transcription of surfactant protein B and thereby promote lung maturation.…”

Interdependent TTF1 - ErbB4 interactions are critical for surfactant protein-B homeostasis in primary mouse lung alveolar type II cells

“…In the lung, both TTF-1 and ErbB4 protein have important roles in promoting surfactant protein expression (Boggaram 2009;Zscheppang 2011). Our previous experiments in fetal murine ATII cells showed that there is an interaction between TTF-1 and ErbB4 (Zscheppang 2013).…”

“…To examine the effects of HER4 and Nkx2.1 (the genes encoding for ErbB4 and TTF-1) overexpression on SP-B, ErbB4, and TTF-1 protein expression levels, MLE-12 cells and primary fetal ATII cells were transfected with plasmid expressing human ErbB4 (HER4), or Nkx2.1, or an empty control construct (EGFP) (Zhou 2008;Zscheppang 2011Zscheppang , 2013. The MLE-12 cells were only transfected with Nkx2.1 or EGFP, since we have already published the effects of ErbB4 overexpression in MLE-12 cells on surfactant protein expression (Zscheppang 2013).…”

“…We here show negative feedback regulation between TTF-1 and ErbB4, and speculate that TTF-1 plays a key role in compensating for ErbB4 loss to maintain Sftpb expression. (Lee 2002;Williams 2004) were used as previously published (Zscheppang 2011). pRC/CMV/Nkx2.1 (Nkx2.1 expression plasmid) was kindly provided by Dr. Jeffrey Whitsett (Cincinnati Children's Hospital Medical Center, Cincinnati, OH) (Zhou 2008).…”

Human Epidermal Growth Factor Receptor Signaling in Acute Lung Injury

“…In the fetal lung, HER4 activation promotes ATII proliferation (66) and fetal lung growth, and genetic deletion of HER4 results in hypoplastic lungs similar to those observed in bronchopulmonary dysplasia (67). Surfactant production, a key physiological function of ATII cells, is regulated by HER4 in the developing lung (66,68). Given these critical roles for HER receptors in pulmonary organogenesis, these pathways are likely to play important roles in the setting of ALI and repair.…”