SDF and GABA interact to regulate axophilic migration of GnRH neurons

Abstract

SummaryStromal derived growth factor (SDF-1) and gamma-aminobutyric acid (GABA) are two extracellular cues that regulate the rate of neuronal migration during development and may act synergistically. The molecular mechanisms of this interaction are still unclear. Gonadotropin releasing hormone-1 (GnRH) neurons are essential for vertebrate reproduction. During development, these neurons emerge from the nasal placode and migrate through the cribriform plate into the brain. Both SDF-1 and GABA have been shown to regulate the rate of GnRH neuronal migration by accelerating and slowing migration, respectively. As such, this system was used to explore the mechanism by which these molecules act to produce coordinated cell movement during development. In the present study, GABA and SDF-1 are shown to exert opposite effects on the speed of cell movement by activating depolarizing or hyperpolarizing signaling pathways, GABA via changes in chloride and SDF-1 via changes in potassium. GABA and SDF-1 were also found to act synergistically to promote linear rather than random movement. The simultaneous activation of these signaling pathways, therefore, results in tight control of cellular speed and improved directionality along the migratory pathway of GnRH neurons.

Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice

“…Signaling via stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 is required for survival and migration of GnRH neurons during embryonic development [100,101]. It has been shown that simultaneous activation by GABA and SDF-1 acts synergistically to stabilize linear rather than random movement of migratory GnRH neurons [102]. Our data indicate that CXCR4 is also expressed in adult GnRH neurons at the mRNA level and exhibits male-specific upregulation.…”

CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration

“…In addition, omission of the primary antibody (single stain) resulted in no detectable signal and omission of the second primary (double stain) resulted in no doublelabeled structures (data not shown). Pictures were taken as previously described (20,32,34). Fluorescent images were taken on a spinning disk confocal system CSU10 (Yokogawa) mounted on an Eclipse TE200 microscope (Nikon) using an EMCCD ImageM digital camera (Hamamatsu) with I-Vision software (Biovision).…”

“…Images were taken with an ELWD 20x objective (Nikon). Both linear distance and total distance were measured as previously described (20,34). Total distance reflects the entire route that the cell moved while linear distance equals the change between the first position and final position.…”

“…Distance traveled was calculated from the X and Y coordinates of the cell center plotted in ImageJ for each frame (total) or first and last frame (linear). Live imagining data was compared by Mann-Whitney U test (20,34), and considered significantly different if P Ͻ .05.…”

“…For this analysis, explants from 2-3 different culture dates were fixed at 5div and stained for GnRH and/or peripherin to assess overall GnRH neuronal migration and olfactory axon outgrowth (36). For control vs. CCDC141 siRNA treated explants, the distance that GnRH cells migrated (N ϭ 4 explants/group) and the 20 olfactory axon terminals farthest press.endocrine.org/journal/endo from the center of each explant (N ϭ 3 explants/group) were measured and compared as previously reported (20,34). Brightfield images in Figure 6A, B were corrected for uneven illumination with a high-pass filter.…”