Distinct contributions of calmodulin-encoding genes to the migration and development of neocortical layer 4 neurons

Calcium signaling plays essential roles in neocortical development, including neurogenesis, neuronal migration, axonal pathfinding, and synaptogenesis. Among these processes, neuronal migration is critical for positioning laminar subtype neurons within the six-layered cortical architecture. Despite its importance, the precise spatiotemporal coordination of calcium-mediated signaling during cortical neuron migration remains poorly understood. Here, we investigated the roles of Calm1, Calm2, and Calm3, which encode the identical protein calmodulin, in the migration of prospective neocortical layer 4 neurons. Loss-of-function analyses revealed that Calm1, but not Calm2 or Calm3, is essential for the migration and proper positioning of layer 4 neurons. In contrast, the loss of either Calm1 or Calm2 disrupted layer 4 neuronal identity, suggesting a cooperative role in fate specification. These findings uncover distinct yet complementary functions of calmodulin-encoding genes in regulating the migration and identity of layer 4 neurons during neocortical development.