A research group at the University of Tokyo has elucidated for the first time the principle of formation of the concentration gradient of the Sonic Hedgehog (SHH) protein, which is important for maintaining five fingers.
SHH protein is one of the morphogenic factors (morphogens), and by forming a concentration gradient in tissues at the early stage of development, the concentration becomes a coordinate, so to speak, and plays a role in determining the morphology of organs in vivo.
In this study, we found that in mice with dysfunction of KIF3B, a kinesin molecular motor responsible for intracellular transport of substances, the concentration gradient of SHH protein in the limb buds, which are the primordia of fetal limbs, was disrupted, leading to polydactyly. I discovered by chance thatSHH proteins in normal mouse limb buds exist as aggregates in the center and diffuse as small particles at the periphery, whereas SHH proteins in polydactyl mice are present throughout the limb buds (central It is said that it diffused as small particles (both at the edge and at the outer edge).
We identified that PI3K signaling is involved in the differential behavior of this SHH protein.Normally, KIF3B carries and activates an enzyme that terminates PI3K signaling (Talpid3), which attenuates PI3K signaling in the central region of limb buds and SHH proteins are incorporated into aggregates.However, in KIF3B-deficient mice, defective Talpid3 transport activates PI3K signaling, and SHH proteins are released and diffuse outside the cell.
Based on this mechanism, the research group proposed an "athletic stadium model" of SHH protein concentration gradient formation.A limb bud can be regarded as a track consisting of two layers, a ``runway'' in the outer edge and a ``sandbox'' in the center. PI3K signal intensity is high in the track but low in the sandbox, and the sandbox has a mechanism that traps the SHH protein inside the cell. He explained that the SHH protein is gradually trapped in the sandbox as it travels along the track, creating an SHH concentration gradient.
The elucidation of how the SHH concentration gradient is formed is an achievement that leads to the fundamental principle of how the human body is made.In addition, the secretion control mechanism of the SHH protein is expected to be applied to various clinical applications such as the development of anticancer drugs.
Paper information:[Developmental Cell] KIF3B promotes a PI3K signaling gradient causing changes in a Shh protein gradient and suppressing polydactyly in mice