Olfactory ensheathing cells form the microenvironment of migrating GnRH‐1 neurons during mouse development

Abstract

During development, GnRH-1 neurons differentiate extracerebraly from the nasal placode and migrate from the vomeronasal organ to the forebrain along vomeronasal and terminal nerves. Numerous studies have described the influence of different molecules on the migration of GnRH-1 neurons, however, the role of microenvironment cells remains poorly understood. This study used GFAP-GFP transgenic mice to detect glial cells at early developmental stages. Using nasal explant cultures, the comigration of glial cells with GnRH-1 neurons was clearly demonstrated. This in vitro approach showed that glial cells began migrating from the explants before GnRH-1 neurons. They remained ahead of the GnRH-1 migratory front and stopped migrating after the GnRH-1 neurons. The association of these glial cells with the axons combined with gene expression analysis of GFAP-GFP sorted cells enabled them to be identified as olfactory ensheathing cells (OEC). Immunohistochemical analysis revealed the presence of multiple glial cell-type markers showing several OEC subpopulations surrounding GnRH-1 neurons. Moreover, these OEC expressed genes whose products are involved in the migration of GnRH-1 neurons, such as Nelf and Semaphorin 4. In situ data confirmed that the majority of the GnRH-1 neurons were associated with glial cells along the vomeronasal axons in nasal septum and terminal nerves in the nasal forebrain junction as early as E12.5. Overall, these data demonstrate an OEC microenvironment for migrating GnRH-1 neurons during mouse development. The fact that this glial cell type precedes GnRH-1 neurons and encodes for molecules involved in their nasal migration suggests that it participates in the GnRH-1 system ontogenesis.

Shaping the Reproductive System: Role of Semaphorins in Gonadotropin-Releasing Hormone Development and Function

“…As such, the role of these cells in the etiology of the defects observed in KS needs to be further investigated. Notably, several guidance molecules known to be crucial for controlling GnRH neuronal migration, such as NELF/Jacob, SDF-1α, Sema3A and Sema4D [23,43,44,45], are expressed by OECs [38,46,47] and this list is likely to lengthen in the coming years.…”

“…Interestingly, in this region, Sema3A is also expressed by olfactory ensheathing cells (OECs), which enwrap and guide olfactory nerves toward the olfactory bulbs [23,37]. During embryonic development, GnRH neurons travel together with other neuronal cells apposed to growing fibers and OECs both in vivo and in vitro, forming the so-called migratory mass that emerges from the presumptive VNO [38,39,40]. …”

“…1c). In addition, it has recently been shown that besides the nasal mesenchyme, the OECs represent a major source of Sema4D production at these anatomical locations [38]. …”

Role of Glia in the Regulation of Gonadotropin-Releasing Hormone Neuronal Activity and Secretion

“…While astrocytes may also be implicated in the early development of the GnRH system [14,15] and in the control of neuronal circuits regulating the activity of GnRH neurons, notably in the arcuate nucleus (see [16] for review), here we will focus only on the direct molecular and cellular interactions that occur between glial cells and GnRH neurons during postnatal development.…”

Polarized Distribution of Active Myosin II Regulates Directional Migration of Cultured Olfactory Ensheathing Cells

“…During development, derived from the olfactory placode, OECs migrate out of the olfactory epithelium together with growing olfactory sensory axons from the lamina propria, and accumulate as a superficial mass upon reaching the telencephalic vesicle at embryonic day (E) E13-E18 in rats, contributing to the formation of presumptive olfactory nerve layer 3–6 . During this process, OECs pioneer the olfactory nerve pathway and provide a conductive substrate for the growth of primary olfactory axons, and are required for embryonic olfactory axon targeting and the migration of gonadotropin-releasing hormone neurons 7–10 . Stimulation of OEC motility enhances olfactory axon growth 3, 11, 12 .…”