# Integrins in the Developing Lung

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $643,288

## Abstract

PROJECT SUMMARY
 Human and murine lung development requires the coordinated efforts of the lung epithelium with the
surrounding extracellular matrix (ECM), but the ECM-directed mechanisms that govern epithelial cell behavior
in the lung remain undefined. In epithelial tissues, integrins serve as receptors for the basement membrane
components collagen and laminins (LMs), with LMs being the most important ECM protein for lung
organogenesis. Lung epithelial cells bind to LMs through integrins α3β1, α6β1, and α6β4. Recent studies
reported that mutations in these integrins cause pulmonary hypoplasia or neonatal emphysema complicated by
abnormal airways, suggesting they play a major role in human developmental lung diseases.
 To investigate the role of LM-binding integrins, we generated lung epithelial specific integrin deletions.
Deletion of both the β1 and α6 subunits resulted in marked branching defects and early death. Deletion of α3
caused only minor airway branching disruption. β4 deficient mice exhibited normal branching but, surprisingly,
were also perinatal lethal. The β4 histological examination was notable for proteinaceous material filling the
airways and lack of cilia, similar to α6 deficient mice, suggesting their demise resulted from airway dysfunction.
 Pathway analysis of α6 deficient lung sequencing data revealed disruptions in BMP signaling, a critical
pathway for airway branching. BMP receptor expression was increased in α6-null epithelial cells, but BMP
target gene expression remained markedly reduced, implicating α6-containing integrins in regulation of the
BMP pathway in the fetal lung. Consistent with loss of cilia in β4 deficient mice, β4-null epithelial cells exhibited
reduced expression of transcription factors linked to MCC terminal differentiation. As a critical component of
hemidesmosomes, α6β4 controls tight adhesion to the basement membrane and connects with the
intracellular keratin intermediate filaments. Keratin also forms a support network apically for cilia, suggesting
that α6β4 regulates keratin organization critical for terminal differentiation of MCCs in the lung. Taken together,
these findings indicate that: 1) α6β1 is the principal integrin required for airway branching likely through BMP
signaling and 2) α6β4 regulates terminal differentiation of MCCs. Based on preliminary data, we propose the
hypothesis that α6-containing integrins are critical integrins for fetal lung development through
regulation of BMP signaling during airway branching and terminal differentiation of multi-ciliated
epithelial cells.
AIM 1: Determine the mechanisms whereby α6-containing integrins regulate lung branching
morphogenesis.
AIM 2: Define the mechanisms whereby α6-containing integrins regulate BMP signaling during fetal
lung development.
AIM 3: Identify the role of α6β4 integrin in airway epithelial cell differentiation.

## Key facts

- **NIH application ID:** 10420896
- **Project number:** 1R01HL163195-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Erin J Plosa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $643,288
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420896

## Citation

> US National Institutes of Health, RePORTER application 10420896, Integrins in the Developing Lung (1R01HL163195-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10420896. Licensed CC0.

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