RRC ID 72834
Author Wang S, Tanaka Y, Xu Y, Takeda S, Hirokawa N.
Title KIF3B promotes a PI3K signaling gradient causing changes in a Shh protein gradient and suppressing polydactyly in mice.
Journal Dev Cell
Abstract Digit determination in limb buds is driven by a posteriorizing Sonic hedgehog (Shh) protein gradient; however, the mechanism regulating this is unclear. Here, we propose a diffusion-and-trapping hypothesis for Shh gradient formation based on data from the preaxial polydactyly phenotype of KIF3B motor hypomorphic mice. In the limb buds of these mice, a distal-to-proximal gradient of fibroblast growth factor (FGF) and phosphatidylinositol 3-kinase (PI3K) signaling and a posterior-to-anterior gradient of Shh were disorganized. This phenotype was reproduced by transplanting FGF8b-soaked beads. At the subcellular level, KIF3B transported the phosphatase and tensin homolog (PTEN)-like phosphatase Talpid3 to terminate PI3K signaling. High and low PI3K signaling strengths differentially sorted endocytosed Shh toward exosome-like particles and cytonemal punctata, respectively. These results indicate that the Shh-containing particles undergo either the diffusional movement in the periphery or cytonemal trapping in the center and form a spatial gradient along the periphery of developing limb buds.
Volume 57(19)
Pages 2273-2289.e11
Published 2022-10-10
DOI 10.1016/j.devcel.2022.09.007
PII S1534-5807(22)00637-2
PMID 36220081
MeSH Animals Extremities Fibroblast Growth Factors / metabolism Gene Expression Regulation, Developmental Hedgehog Proteins* / metabolism Kinesins Limb Buds / metabolism Mice Phosphatidylinositol 3-Kinases / genetics Phosphoric Monoester Hydrolases / genetics Polydactyly* / genetics Polydactyly* / metabolism Tensins / genetics Tensins / metabolism
IF 10.092
Human and Animal Cells NIH/3T3(RCB2767)