meis1 regulates cyclin D1 and c-myc expression, and controls the proliferation of the multipotent cells in the early developing zebrafish eye.
During eye development, retinal progenitors are drawn from a multipotent, proliferative cell population. In Drosophila the maintenance of this cell population requires the function of the TALE-homeodomain transcription factor Hth, although its mechanisms of action are still unknown. Here we investigate whether members of the Meis gene family, the vertebrate homologs of hth, are also involved in early stages of eye development in the zebrafish. We show that meis1 is initially expressed throughout the eye primordium. Later, meis1 becomes repressed as neurogenesis is initiated, and its expression is confined to the ciliary margin, where the retinal stem population resides. Knocking down meis1 function through morpholino injection causes a delay in the G1-to-S phase transition of the eye cells, and results in severely reduced eyes. This role in cell cycle control is mediated by meis1 regulating cyclin D1 and c-myc transcription. The forced maintenance of meis1 expression in cell clones is incompatible with the normal differentiation of the meis1-expressing cells, which in turn tend to reside in undifferentiated regions of the retinal neuroepithelium, such as the ciliary margin. Together, these results implicate meis1 as a positive cell cycle regulator in early retinal cells, and provide evidence of an evolutionary conserved function for Hth/Meis genes in the maintenance of the proliferative, multipotent cell state during early eye development.
Bessa
José
J
CABD, Consejo Superior de Investigaciones Cientificas-Universidad Pablo de Olavide, Seville, Spain.
Tavares
Maria J
MJ
Santos
Joana
J
Kikuta
Hiroshi
H
Laplante
Mary
M
Becker
Thomas S
TS
Gómez-Skarmeta
José Luis
JL
Casares
Fernando
F
D000818:Animals; D002454:Cell Differentiation; D019938:Cyclin D1 / Q000235:genetics*; D017931:DNA Primers; D004625:Embryo, Nonmammalian / Q000502:physiology*; D005123:Eye / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc; D018398:Homeodomain Proteins / Q000502:physiology*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D010957:Plasmids; D016372:RNA, Antisense; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014158:Transcription, Genetic; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D018398:Homeodomain Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D019938:Cyclin D1