Disruption of Ephrin Signaling Associates with Disordered Axophilic Migration of the Gonadotropin-Releasing Hormone Neurons

Abstract

Ephrin signaling is involved in repulsive and attractive interactions mediating axon guidance and cell-boundary formation in the developing nervous system. As a result of a fortuitous transgene integration event, we have identified here a potential role for EphA5 in the axophilic migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode into the brain along ephrinexpressing vomeronasal axons. Transgene integration in the GNR23 mouse line resulted in a 26 kb deletion in chromosome 5, ϳ67 kb 3Ј to Epha5. This induced a profound, region-specific upregulation of EphA5 mRNA and protein expression in the developing mouse brain. The GnRH neurons in GNR23 mice overexpressed EphA5 from embryonic day 11, whereas ephrin A3 and A5 mRNA levels in olfactory neurons were unchanged. The GnRH neurons were found to be slow in commencing their migration from the olfactory placode and also to form abnormal clusters of cells on the olfactory axons, prohibiting their migration out of the nose. As a result, adult hemizygous mice had only 40% of the normal complement of GnRH neurons in the brain, whereas homozygous mice had Ͻ15%. This resulted in infertility in adult female homozygous GNR23 mice, suggesting that some cases of human hypogonadotropic hypogonadism may result from ephrin-related mutations. These data provide evidence for a role of EphA-ephrin signaling in the axophilic migration of the GnRH neurons during embryogenesis.

Novel Roles and Mechanism for Krüppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells

“…Based on the distribution of ESTs in Unigene (www.ncbi.nlm.nih.gov), Klf16 is more broadly expressed than EphA5 in both mouse and humans. However, expression of both Klf16 and EphA5 has been reported in the cortex, spinal cord, tectum, thalamus, and hippocampus (61)(62)(63)(64). Thus, there is potential for KLF16 to function as a transcriptional regulator of EphA5 in multiple regions of the brain.…”

Stromal Cell-Derived Factor-1 (Chemokine C-X-C Motif Ligand 12) and Chemokine C-X-C Motif Receptor 4 Are Required for Migration of Gonadotropin-Releasing Hormone Neurons to the Forebrain

“…Other possibilities are that CXCR4 signaling or continued migration toward the forebrain may be necessary for the maintenance of GnRH gene expression. In other mutant mice, such as netrin1 Ϫ/Ϫ and ephrin3-5 Ϫ/Ϫ mice, there also were reported losses in immunoreactive GnRH neuron numbers, but in neither case was the cause determined (Schwarting et al, 2004;Gamble et al, 2005). In the future it will be of considerable interest to determine whether SDF-1 provides trophic support for GnRH neurons or MM cells.…”

“…These include GABA, ephrins A3 and A5, and polysialic acid-neural cell adhesion molecule (PSA-NCAM) (Tobet et al, 1996;Fueshko et al, 1998;Yoshida et al, 1999;Gamble et al, 2005), although each of these factors acts on only a subset of GnRH neurons. CNS chemokines have been implicated in attracting GnRH axons toward the median eminence, although the nature of these activities has not been defined further (Rogers et al, 1997;Gill and Tsai, 2006).…”

Factors in Early-Life Programming of Reproductive Fitness

“…However, while the overall content in the adult hypothalamus was suppressed by 25% as compared to control animals [64], this reduction is not sufficiently severe to cause infertility. A loss of more than 85% of GnRH neurons is required to result in female infertility [66]. …”