TENM3 is a transmembrane cell adhesion protein primarily known for its role in neural development and connectivity. In the nervous system, TENM3 regulates establishment of precise neural circuits through homophilic cell adhesion mechanisms, functioning in both pre- and postsynaptic neurons [UniProt]. Specifically, TENM3 is required for proper hippocampal connectivity between CA1 and subicular neurons and controls dendrite morphogenesis and axon targeting in the visual system by regulating ipsilateral retinal mapping to the dorsal lateral geniculate nucleus and superior colliculus [UniProt]. Structurally, TENM3 binds the adhesion GPCR Latrophilin through its YD shell domain, forming trans-cellular complexes that direct neuron migration via contact repulsion-dependent mechanisms 1. Clinically, biallelic TENM3 pathogenic variants cause syndromic microphthalmia 15 (MCOPS15), characterized by microcornea, iris and choroidal coloboma, and global developmental delay 2. TENM3 variants are also associated with isolated microphthalmia and coloboma 3, and represent a differential diagnosis consideration in congenital aniridia 4. Beyond ocular development, TENM3 shows suggestive evidence for involvement in developmental dysplasia of the hip etiopathogenesis 5, and recent studies identify TENM3 as a differentially expressed gene with rare variant sharing in familial eosinophilic esophagitis 6. Notably, dysregulation of TENM3-associated pathways occurs in cancer contexts, including gastric cancer metastasis and prostate cancer perineural invasion 78.