MICROPATTERNED NEUROECTODERM TISSUE MODEL TO STUDY EARLY NEURAL DEVELOPMENT AND PATHOGENESIS

Abstract

Current human neural differentiation model-systems can dictate neuroectoderm (NE) cell fate specification but not their morphogenesis. We report a first instance of directing the formation of a human-specific NE tissue that recapitulates architectural and cellular characteristics of early neural tube morphogenesis. These include having a continuous, polarized epithelium and a distinct invagination-like folding, where the NE cells undergo E-to-N-cadherin switching and apical constriction. This is accomplished by spatiotemporal patterning of the mesoendoderm (ME) that guides self-organization of the adjacent NE. We uncover that TGF signaling emanating from endodermal cells is obligatory in NE tissue folding. Notably, evaluation of NE structural dysmorphia, which is uniquely achievable in our model, allowed for early detection of pathologies mediated by FMR1 silencing in Fragile X Syndrome. Altogether, such unprecedented degree of control over the NE tissue architecture greatly expands the potential applications of human stem cell-modeling for early neural tissue development and disease pathologies.