Loss of PRDM16 Drives Nasal Septal Deviation through Dysregulated TGFβ2 Signaling

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; Prdm16 ^flox/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 Col1a1 ^high / 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 TGFβ2 signaling at the nasal septal deviation site. Specifically, TGFβ2 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. TGFβ2 immunohistochemical staining confirmed increased TGFβ2⁺ 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 TGFβ2 signaling, establishing a mechanistic basis for nasal septal deviation.