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

Abstract

GFRα1, 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.

Untitled

“…GDNF was originally discovered as a survival factor for midbrain dopaminergic neurons and a candidate anti-Parkinson disease agent [41], thereafter focusing research on GDNF receptors on the SNpc and VTA areas that harbor these cells. More recent studies characterized other sites of GFRα1 expression in the mammalian brain, particularly in GABAergic neurons of the cerebral cortex [42,43], cerebellum [44,45], and olfactory bulb [46,47]. Our present findings establish mHb neurons as the cells that express the highest levels of GFRα1 in the adult mouse brain, higher than any other known site of expression, and the first glutamatergic neurons known to require this receptor for appropriate connectivity and function.…”

Growth Factors as Axon Guidance Molecules: Lessons From in vitro Studies

“…The C-Ret receptor is expressed in developing neural crest, cranial ganglia, and later in the developing eye of mouse embryos by whole mount in situ (Pachnis et al, 1993). Other work identified GFRα1 receptor expression in the embryonic olfactory bulb (Zechel et al, 2018) and in developing mouse DRGs along with co-receptor Ret (Chen et al, 2017). Interestingly Ret is also expressed by chemosensory geniculate neurons (Donnelly et al, 2018) and by the trigeminal axons that project to the dental pulp, which in turn expresses GDNF (Donnelly et al, 2019).…”