Loss of PRDM16 Drives Nasal Septal Deviation through Dysregulated TGFβ2 Signaling

Authors

Tashbib, E. T., Hansen, V. L., O'Brien, M., Klee, A., Fadial, E., Pryharski, K., Kulzhanova, G., Lambright, K., Shull, L., Wu, C.-L.

Abstract

Nasal septal deviation affects approximately 20% of newborns globally and 80% individuals in the United States. GWAS have linked PRDM16, a histone methyltransferase, to craniofacial abnormalities, yet its role in nasal septum development remains poorly understood. Global Prdm16 knockout mice (Prdm16-/-) exhibit severe craniofacial defects resembling Pierre Robin Syndrome but are neonatally lethal, precluding their potential applications for postnatal study. To address this, we generated an osteochondral lineage-specific, Prdm16 conditional knockout (Col2a1-Cre; Prdm16flox/flox; cKO) mouse model. Both sexes of cKO mice display significantly shorter nasal bone length, with a sex-dependent increase in nasal bone volume fraction of 12 wk old males. Nasal septal deviation is detectable as early as postnatal day 15 and progresses with age. Single-cell RNA sequencing (scRNA-seq) of 4 wk old nasal septal cartilage revealed a marked shift in chondrocyte composition: Mgp+ chondrocytes were substantially reduced, while Col10a1+/Serpina3n+ hypertrophic chondrocytes were dramatically increased, indicating PRDM16 regulates chondrocyte phenotypes. Spatial transcriptomics localized Mgp+ chondrocytes and Col1a1high/Col3a1+ fibrotic cells to the septal cartilage-bone interface (the site of deviation in cKO mice). Intercellular communication analyses revealed a switch in dominant sender cells from the fibrotic population in WT to Mgp+ chondrocytes in cKO. MultiNicheNet bioinformatic analyses identified elevated TGF{beta}2 signaling at the nasal septal deviation site. Specifically, TGF{beta}2 secreted by Mgp+ chondrocytes was predicted to promote Col1a1/Col1a2 expression, resulting in fibrotic extracellular matrix (ECM) deposition and osteogenesis; consistent with elevated RUNX2 in cKO mice. TGF{beta}2 immunohistochemical staining confirmed increased TGF{beta}2 cells in the fibrous ECM and apical nasal cartilage of cKO, but not WT mice. Loss of PRDM16 also increased chondrocyte apoptosis at 4 and 12 wks of age. These findings demonstrate that loss of PRDM16 drives hypertrophic and fibrotic remodeling of nasal septal cartilage through dysregulation of TGF{beta}2 signaling, establishing a mechanistic basis for nasal septal deviation.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Jul 2026.

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