Expression of Neurotrophins and Its Receptors During Fetal Development in the Human Cochlea

We determined the relative expression levels of the receptors <i>TrkA</i>, <i>TrkB</i>, <i>TrkC</i>, and <i>p75^NTR</i> and ligands <i>BDNF</i>, <i>NT-3</i>, <i>NGF</i>, and <i>NT-4</i> with RNAseq analysis on fetal human inner ear samples, located TrkB and TrkC proteins, and quantified <i>BDNF</i> with in situ hybridization on histological sections between gestational weeks (GW) 9 to 19. Spiral ganglion neurons (SGNs) and satellite glia appear to be the main source of <i>BDNF</i> and synthesis peaks twice at GW10 and GW15-GW17. Tonotopical gradients of <i>BDNF</i> revert between GW8 and GW15 and follow a maturation and innervation density gradient in SGNs. <i>NT-3/TrkC</i> follows the same time course of expression as <i>BDNF/TrkB</i>. Immunostaining reveals that TrkB signaling may act mainly through satellite glia, Schwann cells, and supporting cells of Kölliker's organ, while TrkC signaling targets SGNs and pillar cells in humans. The <i>NT-4</i> expression is upregulated when <i>BDNF/NT-3</i> is downregulated, suggesting a balancing effect for sustained TrkB activation during fetal development. The mission of neurotrophins expects nerve fiber guidance, innervation, maturation, and trophic effects. The data shall serve to provide a better understanding of neurotrophic regulation and action in human development and to assess the transferability of neurotrophic regenerative therapy from animal models.