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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Javois, Lorette Claire
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
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
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
Kamberov, Yana G; Wang, Sijia; Tan, Jingze et al. (2013) Modeling recent human evolution in mice by expression of a selected EDAR variant. Cell 152:691-702
Smith, Jeramiah J; Kuraku, Shigehiro; Holt, Carson et al. (2013) Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution. Nat Genet 45:415-21, 421e1-2
Cooper, Kimberly L; Hu, Jimmy Kuang-Hsien; ten Berge, Derk et al. (2011) Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science 332:1083-6
Mao, Junhao; McGlinn, Edwina; Huang, Peng et al. (2009) Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic Hedgehog and promoting outgrowth of the vertebrate limb. Dev Cell 16:600-6
Galloway, Jenna L; Delgado, Irene; Ros, Maria A et al. (2009) A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning. Nature 460:400-4
Cooper, Kimberly L; Tabin, Clifford J (2008) Understanding of bat wing evolution takes flight. Genes Dev 22:121-4
Scherz, Paul J; McGlinn, Edwina; Nissim, Sahar et al. (2007) Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev Biol 308:343-54
Nissim, Sahar; Hasso, Sean M; Fallon, John F et al. (2006) Regulation of Gremlin expression in the posterior limb bud. Dev Biol 299:12-21

Showing the most recent 10 out of 16 publications