Abstract
ABSTRACTSonic hedgehog (Shh), produced in the notochord and floor plate, is necessary for both neural and mesodermal development. To reach the myotome, Shh has to traverse the sclerotome and a reduction of sclerotomal Shh affects myotome differentiation. By investigating loss and gain of Shh function, and floor-plate deletions, we report that sclerotomal Shh is also necessary for neural tube development. Reducing the amount of Shh in the sclerotome using a membrane-tethered hedgehog-interacting protein or Patched1, but not dominant active Patched, decreased the number of Olig2+ motoneuron progenitors and Hb9+ motoneurons without a significant effect on cell survival or proliferation. These effects were a specific and direct consequence of Shh reduction in the mesoderm. In addition, grafting notochords in a basal but not apical location, vis-à-vis the tube, profoundly affected motoneuron development, suggesting that initial ligand presentation occurs at the basal side of epithelia corresponding to the sclerotome-neural tube interface. Collectively, our results reveal that the sclerotome is a potential site of a Shh gradient that coordinates the development of mesodermal and neural progenitors.
Highlights
The sonic hedgehog (Shh) protein plays fundamental roles in the development of the neural tube (NT) and somites (Borycki et al, 1998; Briscoe, 2009; Cairns et al, 2008; Ericson et al, 1997a,b; Gustafsson et al, 2002)
We reported that the traversing of the sclerotome by Sonic hedgehog (Shh) is necessary for myotome differentiation, as misexpression of the high-affinity Shh antagonist Hhip1 in the sclerotome resulted in smaller myotomes expressing desmin accompanied by a corresponding accumulation of Pax7+ progenitors (Kahane et al, 2013) (Fig. 1A,B)
We report that the hemi-NT facing the transfected mesoderm exhibited a 40% reduction in the number of Hb9+ motoneurons compared with control GFP (Fig. 1A′,B′,C, P
Summary
The sonic hedgehog (Shh) protein plays fundamental roles in the development of the neural tube (NT) and somites (Borycki et al, 1998; Briscoe, 2009; Cairns et al, 2008; Ericson et al, 1997a,b; Gustafsson et al, 2002). Its signaling is initiated by binding of the ligand to the transmembrane receptor Patched (Ptc), that represses the pathway in its absence (Goodrich et al, 1997; Hidalgo and Ingham, 1990; Ingham et al, 1991; Johnson et al, 1996). Ligand binding to Ptc abrogates its repressive effect on Smoothened, a key effector essential for Hedgehog signal transduction (van den Heuvel and Ingham, 1996). The repressive role of Ptc correlates with its localization in the apical cilia, which function as a signal transduction compartment (Caspary et al, 2007; Rohatgi et al., Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem 9112102, P.O. Box 12272, Israel
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