# Characterization of the role of mesenchymal Hox5 genes in alveologenesis

> **NIH NIH F32** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $16,280

## Abstract

ABSTRACT
Alveologenesis occurs during the last stage of lung development and is responsible for
subdividing the terminal airways of the lungs into alveoli, structures that are critical for efficient
gas exchange in the lung. Defects in this process lead to the formation of simplified alveoli that
are a hallmark of bronchopulmonary dysplasia (BPD), a chronic lung disease that presents in
premature infants treated with mechanical ventilation or oxygen therapy. Although the molecular
mechanisms that regulate alveolar development during postnatal stages are unknown,
mesodermally-derived fibroblasts in the lung mesenchyme have been shown to be critical
drivers of alveologenesis. Published work from our laboratory has demonstrated that all three
Hox5 genes (HoxA5, HoxB5 and HoxC5) are exclusively expressed in the lung mesenchyme,
and loss of all three Hox5 genes leads to severe developmental lung defects and perinatal
death. Four-allele, compound Hox5 mutant mice (Hox5 AabbCc) are born in Mendelian ratios
and their lungs are histologically normal at birth, however, they develop alveolar simplification at
postnatal stages. Consistent with a direct role for Hox5 genes in alveologenesis, the expression
levels of all three Hox5 genes peak during the postnatal stages when alveologenesis is at its
peak. Our laboratory has recently generated a conditional allele for Hoxa5, allowing us to
bypass the neonatal lethality and assess the post-embryonic functions of this group of
regulators. Conditional deletion of Hoxa5 in the lung mesenchyme beginning at birth results in
alveolar simplification postnatally. The addition of null alleles for Hoxb5 and Hoxc5 exacerbate
this defect. Hox5 conditional mutant lungs exhibit abnormal myofibroblast distribution, shape
and impaired function, and the elastin network required for proper alveologenesis fails to form.
Unbiased RNAseq analyses reveal gene expression changes in categories associated with cell
adhesion and extracellular matrix. Immunofluorescence and western blot analyses demonstrate
that both the basement membrane and extracellular matrix components are expressed normally
in Hox5 conditional mutants. However, mutant fibroblasts exhibit significant adhesion defects in
culture, and preliminary data show loss of Integrin5 expression in fibroblasts derived from
Hox5 conditional mutants. Collectively, our data indicate that Hox5 genes regulate the proper
differentiation and function of mesenchymal fibroblasts and control lung matrix formation critical
for alveologenesis. Using genetics, I plan to elucidate the cellular and molecular mechanisms of
Hox5 regulation of lung mesenchyme in alveologenesis.

## Key facts

- **NIH application ID:** 9942490
- **Project number:** 5F32HL140969-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Leilani Marie Marty-Santos
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $16,280
- **Award type:** 5
- **Project period:** 2018-06-01 → 2020-08-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942490

## Citation

> US National Institutes of Health, RePORTER application 9942490, Characterization of the role of mesenchymal Hox5 genes in alveologenesis (5F32HL140969-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9942490. Licensed CC0.

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