Targeted Disruption of NeuroD, a Proneural Basic Helix-Loop-Helix Factor, Impairs Distal Lung Formation and Neuroendocrine Morphology in the Neonatal Lung

Abstract

Despite the importance of airspace integrity in vertebrate gas exchange, the molecular pathways that instruct distal lung formation are poorly understood. Recently, we found that fibrillin-1 deficiency in mice impairs alveolar formation and recapitulates the pulmonary features of human Marfan syndrome. To further elucidate effectors involved in distal lung formation, we performed expression profiling analysis comparing the fibrillin-1-deficient and wild-type developing lung. NeuroD, a basic helix-loop-helix transcription factor, fulfilled the expression criteria for a candidate mediator of distal lung development. We investigated its role in murine lung development using genetically targeted NeuroD-deficient mice. We found that NeuroD deficiency results in both impaired alveolar septation and altered morphology of the pulmonary neuroendocrine cells. NeuroD-deficient mice had enlarged alveoli associated with reduced epithelial proliferation in the airway and airspace compartments during development. Additionally, the neuroendocrine compartment in these mice manifested an increased number of neuroepithelial bodies but a reduced number of solitary pulmonary neuroendocrine cells in the neonatal lung. Overexpression of NeuroD in a murine lung epithelial cell line conferred a neuroendocrine phenotype characterized by the induction of neuroendocrine markers as well as increased proliferation. These results support an unanticipated role for NeuroD in the regulation of pulmonary neuroendocrine and alveolar morphogenesis and suggest an intimate connection between the neuroendocrine compartment and distal lung development.

Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice

“…Remarkably, histopathologic analysis at postnatal days 1-5 showed no significant differences in alveolar formation [25] between WT and KO mice ( Figure 1E). However, lung sections at postnatal day 7 revealed significant enlargement of the alveolar airspace in KO mice and this became more pronounced by day 10 ( Figure 1E), as quantitatively confirmed by chord length measurements (Supplementary information, Figure S2).…”

Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis

“…Finally, we have described a Notch expression boundary at the NEB, where Dll1 and Dll4 are expressed in PNEC cells, Jagged1 is expressed in neighboring epithelial cells, and Notch receptors are expressed in multiple cell types. The NEB and related bronchoalveolar junctions are thought to represent stem cell niches (26) as well as signaling centers that control distal lung development (36). Although Lfng mutation does not affect specification of PNEC as judged by expression of Mash1 and CGRP, by analogy to its role in central nervous system development, it may affect stem cell differentiation kinetics in this context (37).…”

Unravelling the biology of SCLC: implications for therapy

“…ASCL1 drives the expression of many proto-oncogenes implicated in SCLC progression and cell survival, including MYCL1 , RET , SOX2 , NF-IB , and BCL2 (REFS 39,50). Although NEUROD1 does not seem to be required for the tumorigenesis of classic subtype SCLC, this transcription factor has been shown to induce migratory signalling pathways in human SCLC cells 51 , and can activate a neuroendocrine differentiation programme in a mouse lung epithelial (non-neuroendocrine) cell line 52 .…”