Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis.
Pax6 is a pivotal regulator of eye development throughout Metazoa, but the direct upstream regulators of vertebrate Pax6 expression are unknown. In vertebrates, Pax6 is required for formation of the lens placode, an ectodermal thickening that precedes lens development. Here we show that the Meis1 and Meis2 homeoproteins are direct regulators of Pax6 expression in prospective lens ectoderm. In mice, Meis1 and Meis2 are developmentally expressed in a pattern remarkably similar to Pax6 and their expression is Pax6-independent. Biochemical and transgenic experiments reveal that Meis1 and Meis2 bind a specific sequence in the Pax6 lens placode enhancer that is required for its activity. Furthermore, Pax6 and Meis2 exhibit a strong genetic interaction in lens development, and Pax6 expression is elevated in lenses of Meis2-overexpressing transgenic mice. When expressed in embryonic lens ectoderm, dominant-negative forms of Meis down-regulate endogenous Pax6. These results contrast with those in Drosophila, where the single Meis homolog, Homothorax, has been shown to negatively regulate eye formation. Therefore, despite the striking evolutionary conservation of Pax6 function, Pax6 expression in the vertebrate lens is uniquely regulated.
Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Xin
X
Zhang
Adam
A
Friedman
Shaun
S
Heaney
Patricia
P
Purcell
Richard L
RL
Maas
D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D015153:Blotting, Western; D002642:Chick Embryo; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004475:Ectoderm / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005136:Eye Proteins; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019076:Transgenes
D018076:DNA, Complementary; D005136:Eye Proteins; D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; C102641:Mrg1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D004247:DNA