Cell-autonomous role of GFRα1 in the development of olfactory bulb GABAergic interneurons.

Sabrina Zechel,Carlos F Ibáñez,Diana Fernandez-Suarez

doi:10.1242/bio.033753

Abstract

ABSTRACTGFRα1, 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 GFRα1, leaving the mechanism of action of GFRα1 in OB interneuron development unexplained. Here we report that GFRα1 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 GFRα1 in embryonic GABAergic cells recapitulated the cell losses observed in global Gfra1 knockouts at birth. GFRα1 was also required for the sustained generation and allocation of OB interneurons in adulthood. Conditional loss of GFRα1 altered the migratory behaviour of neuroblasts along the rostral migratory stream (RMS) as well as RMS glial tunnel formation. Together, these data indicate that GFRα1 functions cell-autonomously in subpopulations of OB interneuron precursors to regulate their generation and allocation in the mammalian OB.

Highlights

In the mammalian forebrain, most subpopulations of GABAergic interneurons originate in distant neurogenic areas and migrate to their final locations following trajectories that are, for the most part, tangential to the brain surface
GFRα1 expression in olfactory bulb (OB) GABAergic interneuron precursors of the embryonic septum, olfactory primordium and adult SVZ The precursors of OB GABAergic interneurons are generated in the lateral ganglionic eminence (LGE), septum and olfactory primordium (OBp) during early embryonic stages and in the subventricular zone (SVZ) at later embryonic stages and throughout adulthood (Lois and Alvarez-Buylla, 1994; Luskin, 1993, 1998)
In order to identify cell precursors of OB interneurons in postnatal adult SVZ, we performed immunohistochemistry on sections through the lateral wall of the lateral ventricle and detected significant overlap between green fluorescent protein (GFP) and GABA (Fig. 1B). These results indicated that GFRα1 is expressed in subpopulations of precursors of OB GABAergic interneurons at both embryonic and adult stages

Summary

Introduction

In the mammalian forebrain, most subpopulations of GABAergic interneurons originate in distant neurogenic areas and migrate to their final locations following trajectories that are, for the most part, tangential to the brain surface. In the glomerular layer (GL) of the OB, interneurons expressing tyrosine hydroxylase (TH), calbindin (CB) and calretinin (CR) are generated sequentially in waves during early embryonic stages, later. While the septum generated mostly GL CR-positive cells, the LGE produced all major GL subpopulations, as well as CR interneurons destined to the granule cell layer (GR) (Qin et al, 2017). The molecular signals that control the generation, migration, allocation and differentiation of GABAergic interneurons destined for the OB are incompletely understood

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