Role of Hypothalamic Glycine Receptors in Regulation of Male Sexual Behavior in Rats

Callosal axon guidance during cerebral cortex development is complicated and far from being fully understood. Previous work in our lab has shown that basic helix loop helix transcription factors Neurod2 and Neurod6 are essential regulators for the fasciculation and guidance of callosal axons. Here we use acallosal Neurod2/6 deficient mice as a model system to selectively study callosal axon pathfinding in vivo. We identify Efna4 as transcriptional target of Neurod2/6 in developing neocortex. In utero electroporation of Efna4 into neocortical pyramidal neurons of Neurod2/6 deficient embryos is sufficient to cell-autonomously rescue callosal axon fasciculation and migration along the normal callosal path towards the midsagittal plane. Mechanistically, Efna4 forms a co-receptor complex with Ntrk2 (TrkB) in reverse signaling, and hence regulate AKT cascades in vitro and in vivo via Ntrk2’s SHC-binding tyrosine. Co-electroporation of dominant negative Ntrk2 K571N or Ntrk2 Y515F completely abolishes the ability of Efna4 to rescue callosal axon guidance in Neurod2/6 deficient mice. We also show that the Eph receptors are abundantly expressed in the cortical plate and ventricular zone, but minimally expressed in the intermediated zone (IZ) of the cortex, while ephrinA ligands are largely present on the callosal axons in the IZ. In addition, reverse signaling from extracellular domain of EphA receptors to Efna4 leads to active axonal retraction in vivo. The complementary expression and repulsive interaction of EphA receptors and ephrinA ligands suggest a permissive channel for callosal axon navigation before midline crossing. Thus, ephrinA ligands coordinate fasciculate growth and guidance of callosal axons via interaction with Ntrk2 in cis and with EphA receptors in trans.