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.