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Morphogen or mitogen? Re‐evaluating Sonic Hedgehog function in the developing limb
Author(s) -
Zhu Jianjian,
Nguyen MinhThanh,
Nakamura Eiichiro,
Mackem Susan
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a203-e
Subject(s) - morphogen , sonic hedgehog , numerical digit , biology , limb bud , function (biology) , genetics , signal transduction , mathematics , arithmetic , gene
Sonic hedgehog (Shh) regulates proliferation in many processes but is thought to function mainly as a morphogen in limb bud, regulating both anterior‐posterior digit pattern (digit 1–5, thumb to pinky) and digit number dose‐dependently. Several models for digit patterning by Shh, including the classic spatial morphogen gradient model and more recent expansion‐based temporal gradient model, predict that the highest cumulative levels of Shh signaling (either concentration or over time) specify the most posterior digit. But other recent work indicates that posterior Shh‐expressing cells become refractory in response to Shh signals. We used an inducible Cre and conditional (floxed) Shh allele to determine the temporal sensitivity of digit specification to loss of Shh. Unexpectedly, the observed order of digit loss after recombination at progressively earlier times does not fit well with any current model. Moreover, remaining digits are normal morphologically. An early condensation marker shows that the order of digit loss occurs in exact reverse of the actual normal order in which digit condensations form. Together, the data suggest that Shh is needed to specify digit identity only very early and transiently. Later, Shh acts mainly as a mitogen and/or survival signal that ensures an adequate cell mass to enable the normal number of digit condensations to form. This research was supported by the CCR, NCI, NIH.