The p75 neurotrophin receptor is required for the survival of neuronal progenitors and normal formation of the basal forebrain, striatum, thalamus and neocortex

Abstract

During development, the p75 neurotrophin receptor (p75^NTR) is widely expressed in the nervous system where it regulates neuronal differentiation, migration and axonal outgrowth. p75^NTR also mediates the survival and death of newly born neurons, with functional outcomes being dependent on both timing and cellular context. Here, we show that knockout of p75^NTR from embryonic day 10 (E10) in neural progenitors using a conditional Nestin-Cre p75^NTR floxed mouse causes increased apoptosis of progenitor cells. By E14.5, the number of Tbr2-positive progenitor cells was significantly reduced and the rate of neurogenesis was halved. Furthermore, in adult knockout mice, there were fewer cortical pyramidal neurons, interneurons, cholinergic basal forebrain neurons and striatal neurons, corresponding to a relative reduction in volume of these structures. Thalamic midline fusion during early postnatal development was also impaired in Nestin-Cre p75^NTR floxed mice, indicating a novel role for p75^NTR in the formation of this structure. The phenotype of this strain demonstrates that p75^NTR regulates multiple aspects of brain development, including cortical progenitor cell survival, and that expression during early neurogenesis is required for appropriate formation of telencephalic structures.

Keywords: Brain development; Cortical development; Neuronal progenitor survival; P75 knockout mouse; P75 neurotrophin receptor; Thalamic midline fusion.