title: SHH Protein Variance in the Limb Bud Is Constrained by Feedback Regulation and Correlates with Altered Digit Patterning.
abstract: mRNA variance has been proposed to play key roles in normal development, population fitness, adaptability, and disease. While variance in gene expression levels may be beneficial for certain cellular processes, for example in a cell's ability to respond to external stimuli, variance may be detrimental for the development of some organs. In the bilaterally symmetric vertebrate limb buds, the amount of Sonic Hedgehog (SHH) protein present at specific stages of development is essential to ensure proper patterning of this structure. To our surprise, we found that SHH protein variance is present during the first 10 hr of limb development. The variance is virtually eliminated after the first 10 hr of limb development. By examining mutant animals, we determined that the ability of the limb bud apical ectodermal ridge (AER) to respond to SHH protein was required for reducing SHH variance during limb formation. One consequence of the failure to eliminate variance in SHH protein was the presence of polydactyly and an increase in digit length. These data suggest a potential novel mechanism in which alterations in SHH variance during evolution may have driven changes in limb patterning and digit length.
authors.affiliation: Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610.|Genetics Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610.|Genetics Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: Chanmi
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610.|Genetics Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Lawson
authors.affiliation: Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610.|Genetics Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: Lillian J
authors.initials: LJ
authors.lastname: Svete
authors.affiliation: Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610.|Genetics Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: Lauren M
authors.identifier: 0000-0002-0077-3359
authors.initials: LM
authors.lastname: McIntyre
authors.affiliation: Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610 bharfe@ufl.edu.|Genetics Institute, University of Florida, Gainesville, Florida 32610.
authors.forename: Brian D
authors.identifier: 0000-0002-4410-3525
authors.initials: BD
authors.lastname: Harfe
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D025461:Feedback, Physiological; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D018878:Limb Buds / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019170:Somites / Q000196:embryology / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger
keywords: AER; Shh; limb