Laminin β4 is required for the development of human peripheral sensory neurons

ABSTRACT The extracellular matrix (ECM) provides biophysical and biochemical cues necessary for cellular migration, differentiation and survival during development. Laminins are major ECM proteins consisting of α, β and γ chains. However, the function of laminin β4, encoded by LAMB4, remains unknown. Using human pluripotent stem cells (hPSCs), we characterize the role of LAMB4 in human peripheral sensory neuron (SN) biology. We found that LAMB4 is expressed during early SN specification, and it is required for SN development and survival. To assess clinical relevance, we examined familial dysautonomia (FD), a genetic disorder specifically affecting peripheral neurons. LAMB4 variants previously identified in individuals with severe FD sharply downregulated LAMB4 expression in SNs. Moreover, restoring a healthy ECM rescued the FD-related developmental phenotypes, suggesting that ECM defects contribute significantly to the etiology of FD. Finally, we showed that LAMB4/laminin β4 interacts with laminin α4 and laminin γ3 to form the previously unreported laminin-443 and is required for actin filament formation in SNs. Together, these results identify LAMB4 as a crucial regulator of SN development and survival with clinical implications.