A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3.
Wnt and Sonic Hedgehog (Shh) signals are known to pattern the somite into dermomyotomal, myotomal and sclerotomal cell fates. By employing explants of presomitic mesoderm cultured with constant levels of Wnt3a conditioned medium and increasing levels of Shh, we found that differing levels of Shh signaling elicit differing responses from somitic cells: the lowest level of Shh signaling allows dermomyotomal gene expression, intermediate levels induce loss of dermomyotomal markers and activation of myogenic differentiation, and higher levels induce loss of myotomal markers and activation of sclerotomal gene expression. In addition, we have found that in the presence of high levels of Wnt signaling, instead of inducing sclerotomal markers, Shh signals act to maintain the expression of dermomyotomal and myotomal markers. One of the sclerotomal genes induced by high levels of Shh signaling is Nkx3.2. Forced expression of Nkx3.2 blocks somitic expression of the dermomyotomal marker Pax3 both in vitro and in vivo. Conversely, forced expression of Pax3 in somites can block Shh-mediated induction of sclerotomal gene expression and chondrocyte differentiation in vitro. Thus we propose that varying levels of Shh signaling act in a morphogen-like manner to elicit differing responses from somitic cells, and that Pax3 and Nkx3.2 set up mutually repressing cell fates that promote either dermomyotome/myotome or sclerotome differentiation, respectively.
Cairns
Dana M
DM
Program in Cellular, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Avenue, Boston, MA 02111, USA.
Sato
Mie Elissa
ME
Lee
Philip G
PG
Lassar
Andrew B
AB
Zeng
Li
L
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning; D019070:Cell Lineage; D002642:Chick Embryo; D020219:Chondrogenesis; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019170:Somites / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D015415:Biomarkers; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; D055758:SOX9 Transcription Factor; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein
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