KIF3B promotes a PI3K signaling gradient causing changes in a Shh protein gradient and suppressing polydactyly in mice

Dev Cell. 2022 Oct 10;57(19):2273-2289.e11. doi: 10.1016/j.devcel.2022.09.007.


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.

Keywords: FGF signaling; Kinesin; PI3K signaling; Shh gradient; Sonic hedgehog; limb bud morphogenesis; morphogen gradient; polydactyly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Hedgehog Proteins
  • Kif3b protein, mouse
  • Shh protein, mouse
  • Tensins
  • Fibroblast Growth Factors
  • Phosphoric Monoester Hydrolases
  • Kinesins