Loss of PRDM16 Drives Nasal Septal Deviation through Dysregulated TGFβ2 Signaling

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

doi:10.64898/2026.07.28.741259

bioRxiv · 10.64898/2026.07.28.741259

Loss of PRDM16 Drives Nasal Septal Deviation through Dysregulated TGFβ2 Signaling

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

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Abstract

Nasal septal deviation affects approximiately 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.

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Tashbib, E. T., Hansen, V. L., O'Brien, M., Klee, A., Fadial, E., Pryharski, K., Kulzhanova, G., Lambright, K., Shull, L., Wu, C.-L.. 2026-07-29. Loss of PRDM16 Drives Nasal Septal Deviation through Dysregulated TGFβ2 Signaling. https://doi.org/10.64898/2026.07.28.741259

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