Comparative Analysis of Neurotrophin Receptors and Ligands in Vertebrate Neurons: Tools for Evolutionary Stability or Changes in Neural Circuits?

Abstract

To better understand the role of multiple neurotrophin ligands and their receptors in vertebrate brain evolution, we examined the distribution of trk neurotrophin receptors in representatives of several vertebrate classes. Trk receptors are largely expressed in homologous neuronal populations among different species/classes of vertebrates. In many neurons, trkB and trkC receptors are co-expressed. TrkB and trkC receptors are primarily found in neurons with more restricted, specialized dendritic and axonal fields that are thought to be involved in discriminative or ‘analytical’ functions. The neurotrophin receptor trkA is expressed predominantly in neurons with larger, overlapping dendritic fields with more heterogeneous connections (‘integrative’ or ‘modulatory’ systems) such as nociceptive and sympathetic autonomic nervous system, locus coeruleus and cholinergic basal forebrain. Surveys of trk receptor expression and function in the peripheral nervous system of different vertebrate classes reveal trends ranging from dependency on a single neurotrophin to a more complex dependency on increasing numbers of neurotrophins and their receptors, for example, in taste and inner ear innervation. Gene deletion studies in mice provide evidence for a complex regulation of neuronal survival of sensory ganglion cells by different neurotrophins. Although expression of neurotrophins and their receptors is predominantly conserved in most circuits, increasing diversity of neurotrophin ligands and their receptors and a more complex dependency of neurons on neurotrophins might have facilitated the formation of at least some new neuronal entities.

Spiral Ganglion Neuron Projection Development to the Hindbrain in Mice Lacking Peripheral and/or Central Target Differentiation

“…Absence of cochlear nuclei compromises viability of a small percentage of afferent fibers (Maricich et al, 2009), whereas absence of hair cells eliminates over 90% of all spiral ganglion neurons near term (Fritzsch et al, 2005a) except for areas with limited neurotrophin expression (Matei et al, 2006; Pan et al, 2011). Afferent fibers are, in many cases, necessary for the proper development of their target cells (Akins and Biederer, 2006; von Bartheld and Fritzsch, 2006). Auditory nuclei depend on proper afferent innervation for differentiation and survival (Levi-Montalcini, 1949; Rubel and Fritzsch, 2002) and hair cells require innervation for long-term maintenance (Kersigo and Fritzsch, 2015).…”

Importance of cochlear health for implant function

“…The most common molecules used in laboratory animal experiments to maintain the neural substrate in deaf ears are neurotrophins (Budenz et al, 2012; Ramekers et al, 2012). Neurotrophins are soluble molecules that are secreted by cells and act by binding to cell surface receptors (von Bartheld and Fritzsch, 2006). Once binding occurs, the receptors undergo dimerization and autophosphorylation.…”

On the death Trk

“…The identification of CCM2 as a primary effector of TrkA-induced death and its linkage to disease outcome in neuroblastoma may provide a molecular entry point for elucidation of the enigmatic mechanism of trk-induced death. Moreover, TrkB and TrkC are far more widely expressed in the central nervous system than TrkA (Holtzman et al, 1992;Merlio et al, 1992;von Bartheld and Fritzsch, 2006), thus it is intriguing to speculate that a CCM2-TrkA death pathway might play a role in early elimination of inappropriate or excess precursor cells in the CNS, perhaps similar to the effects of ephrin-EphA signaling on cortical progenitor cell apoptosis (Depaepe et al, 2005). Finally, the possibility of activating the death pathway with other receptors via chimeric mutants of CCM2 may have implications for the targeting of other types of cancer.…”