Secretopathies emerge as a new class of neurocristopathies

Neural crest cells are a transient embryonic population of cells that give rise to a wide range of structures, including craniofacial cartilage and bone, peripheral neurons and glia, as well as components of the cardiac outflow tract, among others. Proper formation, migration and differentiation of NCCs require tightly regulated secretion of signaling molecules, extracellular matrix components and membrane proteins, rendering NCCs particularly reliant on a highly efficient and precisely regulated secretory pathway. Disruption of this pathway has emerged as an important, yet underappreciated, mechanism underlying developmental disease. Mutations in genes encoding components of the secretory machinery have been linked to congenital disorders that affect neural crest-derived tissues, suggesting that impaired intracellular trafficking and cargo export can compromise NCC function. In this review, we propose that such disorders represent a distinct subclass of neurocristopathies, termed secretopathies, in which defects in secretory pathway drive neural crest-associated phenotypes. We further highlight TMED proteins as key cargo receptors within the early secretory pathway whose dysfunction may impact NCC secretory output. Recognizing secretopathies as a novel category of neurocristopathies provides a new framework for understanding the molecular basis of neural crest-related developmental disorders.