title: Cell type-dependent Erk-Akt pathway crosstalk regulates the proliferation of fetal neural progenitor cells.
abstract: Neural progenitor (NP) cells are the multipotent cells that produce neurons and glia in the central nervous system. Compounds regulating their proliferation are key to both understanding brain development and unlocking their potential in regenerative repair. We discuss a chemical screen that unexpectedly identified inhibitors of Erk signaling potently promoting the self-renewing divisions of fetal NP cells. This occurred through crosstalk between Erk and Akt signaling cascades. The crosstalk mechanism is cell type-specific, and is not detected in adult NP cells as well as brain tumor cells. The mechanism was also shown to be independent from the GSK-3 signaling pathway, which has been reported to be a major regulator of NP cell homeostasis and inhibitors to which were also identified in the screen. In vitro Erk inhibition led to the prolonged rapid expansion of fetal NP cells while retaining their multipotency. In vivo inhibitor administration significantly inhibited the neuronal differentiation, and resulted in increased proliferative progenitor cells in the ventricular/subventricular zone (VZ/SVZ) of the embryonic cortex. Our results uncovered a novel regulating pathway for NP cell proliferation in the developing brain. The discovery provides a pharmacological basis for in vitro expansion and in vivo manipulation of NP cells.
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Rhim
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Luo
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Gao
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Tieling
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.|Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Li
authors.affiliation: Weill Cornell Medical College, Cornell University, New York, NY 10065.|Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.|Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.affiliation: Chao Center for BRAIN, Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030.|Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xia
mesh_terms: D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt