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Presenting Author(s) Susan Mackem
Abstract Title Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Sonic Hedgehog.
Full author List Yuting Chen, Vladimir Knezevic, Maria D'Souza, Valerie Ervin, Richard Hutson, Yvona Ward, and Susan Mackem
Text of abstract How different quantitative levels of Sonic hedgehog (SHH) specify the formation of different distinct digit types (identities) in the developing limb remains unclear. SHH signaling protects the Gli3 transcription factor from cleavage to a repressor form. Without Shh, the Gli3 repressor predominates, SHH/Gli3 target genes are repressed, and digit formation largely fails. Eliminating Gli3 renders Shh dispensable for digit formation, but distinct, normal digit identities are lost and polydactyly occurs. Several 5' Hoxd members function downstream of SHH/Gli3 to regulate digit pattern in an additive, semi-redundant manner, through as yet unknown targets. We have found that Gli3 interacts genetically and physically with 5'Hoxd members, converting Gli3 repressor into an activator of its target promoters. In vivo, this interaction promotes formation of digits with distinct, often posterior identities. Certain phenotypic changes due to elevated Hoxd expression are greatly exacerbated by decreased levels of Gli3, yet are reduced or lost in the total absence of Gli3, which is most readily explained by a physical interaction. Our results suggest a stoichiometric model in which varying [Gli3]:[total Hoxd] protein ratios in different parts of the limb bud lead to differential activation of Gli3 target genes that may serve to spatially and/or temporally extend the SHH activity gradient by altering the balance between "effective" Gli3 activating and repressing functions. This model provides a mechanistic basis for the quantitative, dose-dependent nature of Hoxd gene function in regulating digit pattern and may also have implications for the mechanism by which certain human genetic diseases (PHS, PAP), due to Gli3 mutations producing a constitutive repressor form, cause polydactyly. We are currently using a combination of biochemical and genetic approaches to test the model.
Which session is your work most relevant to: Limb patterning