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

Tyro-3, Axl, and Mer are three related receptor protein-tyrosine kinases (R PTKs) characterized by an extracellular domain exhibiting significant amino acid sequence similarity to neural cell adhesion molecules. The molecule G as6 (for growth arrest-specific gene-6) has been shown to activate each of these receptors. Gas6 is expressed extensively in the central nervous syste m (CNS), suggesting that interactions between Gas6 and its receptors are li kely to have physiologically relevant functions. To identify and localize t he relevant Gas6/RPTK pairs, we have characterized the developmental expres sion of Tyro-3, Axl, and Mer in rat CNS using blotting and mRNA in situ hyb ridization analyses. Throughout development, Tyro-3 was the most widely exp ressed 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 e mbryo and increased markedly during early postnatal stages, with a time cou rse paralleling that of synaptogenesis. Axl and Mer were expressed at low b ut relatively constant levels throughout development. In the cerebellum, al l three receptors were found in Purkinje cells, and Tyro-3 was also detecte d in both granule neurons and Bergmann glia. Insofar as Gas6 has been previ ously shown to also be expressed by Purkinje cells, it may be engaged in bo th autocrine and paracrine signaling. The three receptors were also detecte d 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 le vels in CA1 pyramidal neurons and at lower levels in CA3 and was not detect ed in dentate granule neurons. Axl and Mer were found in the molecular laye r of the dentate gyrus and were absent from the pyramidal and dentate granu le neurons. In that Gas6 is expressed throughout the pyramidal cell layer, it may activate these cells in both an autocrine and a paracrine manner. Th ese 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. J. Co mp. Neurol. 425:295-314, 2000. (C) 2300 Wiley-Liss, Inc.