NOSIP (nitric oxide synthase interacting protein) is an E3 ubiquitin ligase essential for forebrain, eye, and craniofacial development 1. Its primary function is negative regulation of nitric oxide (NO) production through two mechanisms: it mediates translocation of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) to the actin cytoskeleton, inhibiting their enzymatic activity 2, and catalyzes monoubiquitination of protein phosphatase 2A (PP2A) catalytic subunits 1. Nuclear import of NOSIP is mediated primarily by transportin 1, with subsequent cytoplasmic export occurring via passive diffusion 3. NOSIP is critical for developmental neurogenesis; knockout mice exhibit reduced cortical thickness, diminished postmitotic neuron formation, and decreased neural progenitor populations 4. Loss of NOSIP causes holoprosencephaly and craniofacial anomalies including cleft palate and cyclopia 1, and disrupts eye development and anterior neural crest cell induction 5. During neutrophil differentiation, NOSIP expression is downregulated to permit increased NO generation 6. Clinically, elevated NOSIP expression in Hirschsprung's disease colon may contribute to enterocolitis by suppressing local NO production 7. NOSIP emerges as a candidate gene for human holoprosencephaly and other developmental disorders.