Cell-autonomous role of GFR?1 in the development of olfactory bulb GABAergic interneurons

Abstract

GFR?1, a receptor for glial cell line-derived neurotrophic factor (GDNF), is critical for the development of the main olfactory system. The olfactory bulb (OB) of Gfra1 knockout mice shows significant reductions in the number of olfactory sensory neurons, mitral and tufted cells, as well as all major classes of OB GABAergic interneurons. However, the latter do not express significant levels of GFR?1, leaving the mechanism of action of GFR?1 in OB interneuron development unexplained. Here we report that GFR?1 is highly expressed in the precursor cells that give rise to all major classes of OB interneurons, but is downregulated as these neurons mature. Conditional ablation of GFR?1 in embryonic GABAergic cells recapitulated the cell losses observed in global Gfra1 knockouts at birth. GFR?1 was also required for the sustained generation and allocation of OB interneurons in adulthood. Conditional loss of GFR?1 altered the migratory behaviour of neuroblasts along the rostral migratory stream (RMS) as well as RMS glial tunnel formation. Together, these data indicate that GFR?1 functions cell-autonomously in subpopulations of OB interneuron precursors to regulate their generation and allocation in the mammalian OB. © 2018. Published by The Company of Biologists Ltd.