Neural tube development depends on notochord-derived Sonic hedgehog released into the sclerotome

Abstract

<jats:title>Abstract</jats:title><jats:p>Sonic hedgehog (Shh), produced in notochord and floor plate, is necessary both for neural and mesodermal development. To reach the myotome, Shh has to traverse the sclerotome. By 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 sclerotome by membrane-tethered hedgehog-interacting protein or by Patched1, but not by dominant active Patched, decreased motoneuron numbers while also compromising myotome differentiation. These effects were a specific and direct consequence of reducing Shh. In addition, grafting notochords in a basal, but not apical location vis-a-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.</jats:p><jats:p>Collectively, our results reveal that the sclerotome is a potential site of a Shh gradient that coordinates development of mesodermal and neural progenitors.</jats:p><jats:sec><jats:title>Summary statement</jats:title><jats:p>Shh that transits through the sclerotome is presented to the neuroepithelium from its basal aspect to affect motoneuron development.</jats:p></jats:sec>

Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma

“…Interestingly, a study by Rantakari et al showed that Palb2 (−/−) mouse embryos revealed a notochord with diffuse and discontinuous morphology (Rantakari et al, 2010), implicating PALB2 in chordoma development. Moreover, a Brca1 (−/−) mouse model demonstrated that abnormalities in Brca1 ‐deficient embryos were most evident in the neural tube (Gowen et al, 1996), the development of which is induced by notochord‐derived sonic hedgehog ( Shh ) signaling (Kahane & Kalcheim, 2020). In line with this, a recent genomic study of 11 chordoma patients demonstrated that SBS3, a mutational signature associated with HR deficiency (HRD) and BRCA1/2 germline mutations, was significantly enriched in advanced chordoma samples (Gröschel et al, 2019), further supporting the potential importance of PALB2/BRCA2‐mediated HR repair in chordoma development.…”

Completion of neural crest cell production and emigration is regulated by retinoic acid-dependent inhibition of BMP signaling

“…For immunostaining, embryos were fixed overnight at 4 °C with 4% formaldehyde (PFA) in phosphate-buffered saline (PBS) (pH 7.4), embedded in paraffin wax and serially sectioned at 8 μm. Immunostaining was performed either on whole mount embryos or on paraffin sections, as previously described (Burstyn-Cohen and Kalcheim, 2002; Kahane and Kalcheim, 2020). Antibodies were diluted in PBS containing 5% fetal bovine serum (Biological Industries Israel, 04-007-1A) and 1% or 0.1% Triton X-100 (Sigma Aldrich Israel, X-100), respectively.…”

“…For immunostaining, embryos were fixed overnight at 4 °C with 4% formaldehyde (PFA) in phosphate-buffered saline (PBS) (pH 7.4), embedded in paraffin wax and serially sectioned at 8 m. Immunostaining was performed either on whole mount embryos or on paraffin sections, as previously described (Burstyn-Cohen and Kahane and Kalcheim, 2020).…”