Abstract
Olfactory ensheathing cells (OECs) are a specialized class of glia, wrapping around olfactory sensory axons that target the olfactory bulb (OB) and cross the peripheral nervous system/central nervous system boundary during development and continue to do so post-natally. OEC subpopulations perform distinct subtype-specific functions dependent on their maturity status. Disrupted OEC development is thought to be associated with abnormal OB morphogenesis, leading to anosmia, a defining characteristic of Kallmann syndrome. Hence, anosmin-1 encoded by Kallmann syndrome gene (KAL-1) might modulate OEC differentiation/maturation in the OB. We performed in ovo electroporation of shRNA in the olfactory placode to knock-down kal in chick embryos, resulting in abnormal OB morphogenesis and loss of olfactory sensory axonal innervation into OB. BLBP-expressing OECs appeared to form a thinner and poorly organized outmost OB layer where SOX10 expressing OECs were completely absent with emergence of GFAP-expressing OECs. Furthermore, in embryonic day 10 chick OB explant cultures, GFAP expression in OECs accumulating along the OB nerve layers was dramatically reduced by recombinant anosmin-1. We then purified immature OECs from embryonic day 10 chick OB. These cells express GFAP after 7days in vitro, exhibiting a multipolar morphology. Overexpression of chick anosmin, exogenous anosmin-1 or FGF2 could inhibit GFAP expression with cells presenting elongated morphology, which was blocked by the FGF receptor inhibitor Su5402. These data demonstrate that anosmin-1 functions via FGF signalling in regulating OEC maturation, thereby providing a permissive glial environment for axonal innervation into the OB during development.
Highlights
Olfactory sensory neurons, whether after damage or as part of normal cell turnover, continually extend axons from the olfactory epithelium, through the lamina propria to enter the outer layer of the olfactory bulb (OB) (Farbman, 1990; Graziadei & Graziadei, 1979)
Since KAL‐1 is absent in the genomes of mouse and rat, other vertebrate species have been employed to investigate the biology of anosmin‐1 during development
Our chick model using in ovo electroporation to knock‐down kal shows that loss of function of anosmin results in abnormal olfactory ensheathing cells (OECs) maturation, suggesting a novel mechanism whereby anosmin‐1 modulates OEC development during olfactory system ontogeny
Summary
Whether after damage or as part of normal cell turnover, continually extend axons from the olfactory epithelium, through the lamina propria to enter the outer layer of the olfactory bulb (OB) (Farbman, 1990; Graziadei & Graziadei, 1979). Recent study demonstrated that OEC maturation is involved in neurite outgrowth of GnRH neurons during migration (Geller et al, 2017) These findings possibly link the OEC development with the aetiology of KS. Anosmin‐1 is expressed in the interneurons and ONL of the developing OB, and has been shown to demonstrate chemoattractive and stimulative properties on axonal branching, neurite outgrowth and neuronal migration (Gonzalez‐Martinez et al, 2004; Hu, Gonzalez‐Martinez, Kim, & Bouloux, 2004; Hu et al, 2009; Legouis, Lievre, Leibovici, Lapointe, & Petit, 1993; Lutz et al, 1994; Soussi‐Yanicostas et al, 1998). As the migration of OEC from the olfactory placode towards the telencephalon occurs before KAL‐1 expression in the presumptive OB, suggesting that anosmin‐1 does not appear essential for initial OEC migration Based on these observations, we hypothesized that anosmin‐1 might modulate OEC maturation, enabling the establishment of stable synaptic connections between olfactory sensory axons and the OB anlage during embryogenesis. Our data provide a novel mechanistic link between loss of function mutations in anosmin‐1 in humans and the resulting severe anosmia
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