Single-cell transcriptomic atlas of the human fetal uveal tract reveals heterogeneity in melanocyte populations

Uveal melanocytes are neural crest-derived cells contributing to ocular pigmentation, yet their developmental heterogeneity and microenvironmental roles remain poorly characterized. We present a single-cell transcriptomic atlas of the human fetal uveal tract, profiling 81,603 cells across 14 cell types from eight eyes at 12 and 20 post-conception weeks. Among 5,142 melanocytes, we identify four subpopulations, including a transcriptionally unique cluster enriched in posterior uveal tissue at later developmental stages. This population expresses NR2F1, FOXC1, and PITX2 alongside extracellular matrix and angiogenic genes and is predicted to communicate with Schwann cells, endothelial cells, and immune populations to modulate the uveal microenvironment. Multiplex immunofluorescence confirms MITF ⁺/FOXC1 ⁺ co-expressing cells in fetal choroidal tissue, validating this population in situ. A refined gene signature from this cluster associates with high-metastatic risk across three independent uveal melanoma cohorts and is enriched in aggressive tumor cell states in single-cell data, implicating developmental program reactivation in disease progression.