The general goal of this project is to understand patterning and morphogenesis during vertebrate embryogenesis, using Sonic hedgehog (Shh) signaling in the limb bud as a model. Building on the results of the previous five years of funding, we have three Specific Aims. The First makes use of an extremely powerful in vitro system we have developed where we can maintain limb bud cells in an undifferentiated state for several weeks and still reconsitute them as a limb bud and assess their morphological potential. We will use this to study the integration of time and dose in establishing threshold responses to Shh activity in patterning the limb and also study how various signals work together to define proximodistal limb pattern.
A second Aim focuses on the role of Shh in controlling the size ofthe limb bud and its synergistic activity with the Hippo/YAP pathway. This part ofthe project will be carried out in mice, using activatable and conditionally deficient alleles of YAP. Mice harboring these alleles will be bred to lines of mice expressing cre recombinase exclusively in the Shh-expressing cells, throughout the limb bud, and in the limb myoblasts, thereby activating or inactivating the YAP/HIPPO pathway specifically in these tissues. Finally, a third Aim will address the important, but poorly understood phenomonom of scaling, wherein the same signaling systems pattern very small or large embryos in an equivelant manner. We will focus on the mechanisms interpreting Shh signaling in the relatively large limb bud of the chick in comparison to the relatively small limb bud of the direct developing frog coqui.
|Hiscock, Tom W; Tschopp, Patrick; Tabin, Clifford J (2017) On the Formation of Digits and Joints during Limb Development. Dev Cell 41:459-465|
|Young, John J; Tabin, Clifford J (2017) Saunders's framework for understanding limb development as a platform for investigating limb evolution. Dev Biol 429:401-408|
|Lau, Mei Sheng; Schwartz, Matthew G; Kundu, Sharmistha et al. (2017) Mutation of a nucleosome compaction region disrupts Polycomb-mediated axial patterning. Science 355:1081-1084|
|Rodrigues, Alan R; Yakushiji-Kaminatsui, Nayuta; Atsuta, Yuji et al. (2017) Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells. Proc Natl Acad Sci U S A 114:3139-3144|
|Uygur, Aysu; Young, John; Huycke, Tyler R et al. (2016) Scaling Pattern to Variations in Size during Development of the Vertebrate Neural Tube. Dev Cell 37:127-35|
|Kamberov, Yana G; Karlsson, Elinor K; Kamberova, Gerda L et al. (2015) A genetic basis of variation in eccrine sweat gland and hair follicle density. Proc Natl Acad Sci U S A 112:9932-7|
|Wong, Siew Fen Lisa; Agarwal, Vikram; Mansfield, Jennifer H et al. (2015) Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs. Proc Natl Acad Sci U S A 112:E4884-93|
|Cooper, Kimberly L; Sears, Karen E; Uygur, Aysu et al. (2014) Patterning and post-patterning modes of evolutionary digit loss in mammals. Nature 511:41-5|
|Tschopp, Patrick; Sherratt, Emma; Sanger, Thomas J et al. (2014) A relative shift in cloacal location repositions external genitalia in amniote evolution. Nature 516:391-4|
|Rodrigues, Alan R; Tabin, Clifford J (2013) Developmental biology. Deserts and waves in gene expression. Science 340:1181-2|
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