Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and Mer in the developing rat central nervous system

Abstract

Tyro-3, Axl, and Mer are three related receptor protein-tyrosine kinases (RPTKs) characterized by an extracellular domain exhibiting significant amino acid sequence similarity to neural cell adhesion molecules. The molecule Gas6 (for growth arrest-specific gene-6) has been shown to activate each of these receptors. Gas6 is expressed extensively in the central nervous system (CNS), suggesting that interactions between Gas6 and its receptors are likely to have physiologically relevant functions. To identify and localize the relevant Gas6/RPTK pairs, we have characterized the developmental expression of Tyro-3, Axl, and Mer in rat CNS using blotting and mRNA in situ hybridization analyses. Throughout development, Tyro-3 was the most widely expressed of the three receptors in the CNS, with Axl and Mer detected in only a limited number of sites in the adult. Tyro-3 expression was low in the embryo and increased markedly during early postnatal stages, with a time course paralleling that of synaptogenesis. Axl and Mer were expressed at low but relatively constant levels throughout development. In the cerebellum, all three receptors were found in Purkinje cells, and Tyro-3 was also detected in both granule neurons and Bergmann glia. Insofar as Gas6 has been previously shown to also be expressed by Purkinje cells, it may be engaged in both autocrine and paracrine signaling. The three receptors were also detected in cerebellar white matter, primarily during myelination. In the cortex, Tyro-3 was expressed at high levels during postnatal development and in the adult. Beginning at P6 in the hippocampus, Tyro-3 was expressed at high levels in CA1 pyramidal neurons and at lower levels in CA3 and was not detected in dentate granule neurons. Axl and Mer were found in the molecular layer of the dentate gyrus and were absent from the pyramidal and dentate granule neurons. In that Gas6 is expressed throughout the pyramidal cell layer, it may activate these cells in both an autocrine and a paracrine manner. These studies provide initial clues for elucidating the cellular functions of the Axl subfamily members and suggest potential complex Gas6/RPTK as well as RPTK/RPTK signaling interactions in the mature and developing CNS.

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

“…Gas6 has the highest affinity for Axl, and in humans Gas6 is the sole ligand for these receptors (Li et al, 1996). Gas6 is expressed and secreted by neurons and endothelial cells; its widespread expression in the CNS suggests that the interaction between Gas6 and its receptor has a relevant physiological function (Li et al, 1996;Prieto et al, 2000). Gas6 signaling can induce varied responses in specific cell types.…”

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

“…OTHER-Given their broad expression patterns, it is likely that TAM receptors perform important functions in numerous other cells types. For example, Tyro-3, Axl, Mer, and their mutual ligand Gas6 are all expressed in the central nervous system but their normal biological activity has not been widely studied in the brain (Lai and Lemke, 1991;Mark et al, 1994;Prieto et al, 1999Prieto et al, , 2000. One exception is an established line of evidence demonstrating a role for Axl in survival and migration of gonadotropin-releasing hormone (GnRH) neurons (Allen et al, 1999(Allen et al, , 2002Nielsen-Preiss et al, 2007).…”

Expressions of Axl and Tyro-3 receptors are under regulation of nerve growth factor and are involved in differentiation of PC12 cells

“…The region-specific expression pattern of Tyro-3 suggests that Tyro-3 may play an important role in the development and the biological functions of CNS. Different from Tyro-3 predominantly expressed in the brain, Axl is found at the highest levels in heart and skeletal muscle, and at a low but relatively constant level in the brain throughout development [5] . Structures of Tyro-3 and Axl are similar, sharing 35% and 63% sequence identities in the extracellular and the intracellular domains, respectively [3] .…”