Migration from a mitogenic niche promotes cell-cycle exit.
During development, neural precursors proliferate in one location and migrate to the residence of their mature function. The transition from a proliferative stage to a migratory stage is a critical juncture; errors in this process may result in tumor formation, mental retardation, or epilepsy. This transition could be the result of a simple sequential process in which precursors exit the cell cycle and then begin to migrate or a dynamically regulated process in which migration away from a mitogenic niche induces precursors to exit the cell cycle. Here, we show, using in vivo and in vitro approaches, that granule cell precursors proliferate when they are exposed to the microenvironment of the external granule cell layer (EGL) and exit the cell cycle as a result of migrating away from this environment. In vivo, granule cell precursors that remain in the EGL because of impaired migration continue to proliferate in the mitogenic niche of the EGL. In vitro, granule cell precursors that are introduced into an organotypic cerebellar slice proliferate preferentially in the EGL. We identify Sonic Hedgehog as a critical component of the EGL mitogenic niche. Together, these data indicate that migration away from a mitogenic niche promotes transition from a proliferative to a nonproliferative, migratory stage.
Choi
Yoojin
Y
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Borghesani
Paul R
PR
Chan
Jennifer A
JA
Segal
Rosalind A
RA
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D053823:Hedgehog Proteins; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism* / Q000494:pharmacology; D014704:Veratrum Alkaloids / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; C492236:Cdk5r1 protein, mouse; D053823:Hedgehog Proteins; D007211:Indoles; C465570:Shh protein, mouse; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D049452:Green Fluorescent Proteins; C007293:DAPI; D010770:Phosphotransferases; D001973:Bromodeoxyuridine; C000541:cyclopamine