PMID- 25514676 OWN - NLM STAT- MEDLINE DCOM- 20160204 LR - 20231213 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 12 DP - 2014 TI - TAM receptors support neural stem cell survival, proliferation and neuronal differentiation. PG - e115140 LID - 10.1371/journal.pone.0115140 [doi] LID - e115140 AB - Tyro3, Axl and Mertk (TAM) receptor tyrosine kinases play multiple functional roles by either providing intrinsic trophic support for cell growth or regulating the expression of target genes that are important in the homeostatic regulation of immune responses. TAM receptors have been shown to regulate adult hippocampal neurogenesis by negatively regulation of glial cell activation in central nervous system (CNS). In the present study, we further demonstrated that all three TAM receptors were expressed by cultured primary neural stem cells (NSCs) and played a direct growth trophic role in NSCs proliferation, neuronal differentiation and survival. The cultured primary NSCs lacking TAM receptors exhibited slower growth, reduced proliferation and increased apoptosis as shown by decreased BrdU incorporation and increased TUNEL labeling, than those from the WT NSCs. In addition, the neuronal differentiation and maturation of the mutant NSCs were impeded, as characterized by less neuronal differentiation (beta-tubulin III+) and neurite outgrowth than their WT counterparts. To elucidate the underlying mechanism that the TAM receptors play on the differentiating NSCs, we examined the expression profile of neurotrophins and their receptors by real-time qPCR on the total RNAs from hippocampus and primary NSCs; and found that the TKO NSC showed a significant reduction in the expression of both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but accompanied by compensational increases in the expression of the TrkA, TrkB, TrkC and p75 receptors. These results suggest that TAM receptors support NSCs survival, proliferation and differentiation by regulating expression of neurotrophins, especially the NGF. FAU - Ji, Rui AU - Ji R AD - Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America; Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America. FAU - Meng, Lingbin AU - Meng L AD - Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America. FAU - Jiang, Xin AU - Jiang X AD - Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China. FAU - Cvm, Naresh Kumar AU - Cvm NK AD - Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America. FAU - Ding, Jixiang AU - Ding J AD - Birth Defects Center, University of Louisville School of Dentistry, Louisville, Kentucky, 40202, United States of America. FAU - Li, Qiutang AU - Li Q AD - Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America. FAU - Lu, Qingxian AU - Lu Q AD - Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America; Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, United States of America. LA - eng GR - R01 EY018830/EY/NEI NIH HHS/United States GR - R01 EY019891/EY/NEI NIH HHS/United States GR - R01-EY018830/EY/NEI NIH HHS/United States GR - R01-EY019891/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20141216 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nerve Growth Factors) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Nerve Growth Factor) RN - 0 (Recombinant Proteins) RN - 0 (Ngfr protein, mouse) RN - 0 (tyrosine receptor kinase A Ig2) RN - EC 2.7.10.1 (Mertk protein, mouse) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, trkA) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (Receptor, trkC) RN - EC 2.7.10.1 (Tyro3 protein, mouse) RN - EC 2.7.10.1 (c-Mer Tyrosine Kinase) RN - 0 (Axl Receptor Tyrosine Kinase) RN - 0 (AXL receptor tyrosine kinase, mouse) SB - IM MH - Animals MH - Apoptosis/genetics MH - Brain-Derived Neurotrophic Factor/biosynthesis MH - Cell Proliferation MH - Cell Survival MH - Cells, Cultured MH - Hippocampus/cytology/metabolism MH - Mice MH - Mice, Knockout MH - Nerve Growth Factors/biosynthesis MH - Neural Stem Cells/*metabolism MH - Neurogenesis/*genetics MH - Proto-Oncogene Proteins/biosynthesis/genetics/*metabolism MH - Receptor Protein-Tyrosine Kinases/biosynthesis/genetics/*metabolism MH - Receptor, trkA/biosynthesis MH - Receptor, trkB/biosynthesis MH - Receptor, trkC/biosynthesis MH - Receptors, Nerve Growth Factor/biosynthesis MH - Recombinant Proteins MH - c-Mer Tyrosine Kinase MH - Axl Receptor Tyrosine Kinase PMC - PMC4267817 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/12/17 06:00 MHDA- 2016/02/05 06:00 PMCR- 2014/12/16 CRDT- 2014/12/17 06:00 PHST- 2014/04/28 00:00 [received] PHST- 2014/11/18 00:00 [accepted] PHST- 2014/12/17 06:00 [entrez] PHST- 2014/12/17 06:00 [pubmed] PHST- 2016/02/05 06:00 [medline] PHST- 2014/12/16 00:00 [pmc-release] AID - PONE-D-14-18573 [pii] AID - 10.1371/journal.pone.0115140 [doi] PST - epublish SO - PLoS One. 2014 Dec 16;9(12):e115140. doi: 10.1371/journal.pone.0115140. eCollection 2014.