Endogenous erythropoietin signaling regulates migration and laminar positioning of upper-layer neurons in the developing neocortex

Abstract

Erythropoietin (EPO), the hypoxia-inducible hematopoietic hormone, has well-established neuroprotective/neurotrophic roles in the developing central nervous system and the therapeutic potential of EPO has been widely explored in clinical studies for treatment of perinatal hypoxic brain lesion as well as prematurity. Here we reveal, that both EPO and EPOR are expressed in the developing rat somatosensory cortex during radial migration and laminar positioning of granular and supragranular neurons. Experimental deregulation of EPO signaling using genetic approaches results in aberrant migration as well as permanent neuronal misplacement leading to abnormal network activity and protracted sensory behavioral deficits. We identify ERK as the downstream effector of the EPO signaling pathway for neuronal migration. These findings reveal a critical role for endogenous EPO signaling in neuronal migration and offer important insights for understanding how temporary deregulation of EPO could results in migration defects leading to abnormal behavior in the adult.