Pax6 and SOX2 form a co-DNA-binding partner complex that regulates initiation of lens development
AUTOR(ES)
Kamachi, Yusuke
FONTE
Cold Spring Harbor Laboratory Press
RESUMO
Pax6 is a key transcription factor in eye development, particularly in lens development, but its molecular action has not been clarified. We demonstrate that Pax6 initiates lens development by forming a molecular complex with SOX2 on the lens-specific enhancer elements, e.g., the δ-crystallin minimal enhancer DC5. DC5 shows a limited similarity to the binding consensus sequence of Pax6 and is bound poorly by Pax6 alone. However, Pax6 binds cooperatively with SOX2 to the DC5 sequence, resulting in formation of a high-mobility form of ternary complex in vitro, which correlates with the enhancer activation in vivo. We observed Pax6 and SOX2-interdependent factor occupancy of DC5 in a chromatin environment in vivo, providing the molecular basis of synergistic activation by Pax6 and SOX2. Subtle alterations of the Pax6-binding-site sequence of DC5 or of the inter-binding-sites distance diminished the cooperative binding and caused formation of a non-functional low-mobility form complex, suggesting DNA sequence-guided and protein interaction-induced conformation change of the Pax6 protein. When ectopically expressed in embryo ectoderm, Pax6 and SOX2 in combination activate δ-crystallin gene and elicit lens placode development, indicating that the complex of Pax6 and SOX2 formed on specific DNA sequences is the genetic switch for initiation of lens differentiation.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=313803Documentos Relacionados
- Stage-dependent modes of Pax6-Sox2 epistasis regulate lens development and eye morphogenesis
- Mutually regulated expression of Pax6 and Six3 and its implications for the Pax6 haploinsufficient lens phenotype
- Pax6 is essential for lens fiber cell differentiation
- Primary defects in the lens underlie complex anterior segment abnormalities of the Pax6 heterozygous eye
- Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis