PRDM16 is necessary for sensory neuronal development and differentiation in the trigeminal ganglion

Cranial neural crest cells (cNCC) generate craniofacial cartilage, bone, and peripheral neurons and glia, and birth defects arise when the cartilage/neuronal/glial progenitors fail to differentiate. PRDM16 is a transcriptional regulator containing both zinc-finger and SET domains, implicated in craniofacial development and orofacial clefting, but its role in cranial sensory ganglion formation has not been defined.

Here, we demonstrate that prdm16 is required for trigeminal ganglion (TG) assembly and sensory neurogenesis from cranial neural crest lineages. In zebrafish, prdm16 is highly expressed in TG and sox10-positive neural crest cells, beginning by 18 h post fertilization (hpf) and persists through the later developmental stage at 48 hpf. Similarly, Prdm16 expression is also found in the mouse TG neurons at embryonic day (E) 18.5. In the prdm16 loss-of-function zebrafish, fewer HuC+ TG neurons are present at 24 hpf and 48 hpf, resulting in reduced overall ganglion volume and area. Live imaging in Tg(sox10:mRFP; elavl3:GFP) embryos demonstrates that similar numbers of sox10+ cNCCs migrate to the TG region in wildtype and mutants; however, reduced trigeminal ganglion cell numbers and area are observed in prdm16-/-. Acetylated β-tubulin immunostaining shows fewer trigeminal axon projections early and an altered projection pattern by 48 hpf. p2rx3b+ defined sensory neuron population displayed reduced signal intensity and decreased cell number in prdm16-/- TG. Transcriptomic analysis of FACS-isolated sox10+ cranial neural crest cells shows reduced expression of key neurogenic and sensory lineage genes. Finally, the role of PRDM16 in trigeminal neurogenesis is conserved across vertebrates: Prdm16^csp1/csp1 mutant mouse embryos also exhibited reduced TG mediolateral diameter, overall area, and fewer HuC+ neurons at E18.5 compared to control.

Together, these data identify Prdm16 as a conserved regulator of trigeminal ganglion growth and sensory neuron differentiation, linking PRDM-family of chromatin regulators to the development of the peripheral sensory nervous system.