[PDF][PDF] Sonic hedgehog is not a limb morphogen but acts as a trigger to specify all digits in mice
Limb patterning by Sonic hedgehog (Shh), via either graded spatial or temporal signal
integration, is a paradigm for" morphogen" function, yet how Shh instructs distinct digit
identities remains controversial. Here, we bypass the Shh requirement in cell survival during
outgrowth and demonstrate that a transient, early Shh pulse is both necessary and sufficient
for normal mouse limb development. Shh response is only short range and is limited to the
Shh-expressing zone during this time window. Shh patterns digits 1–3, anterior to this zone …
integration, is a paradigm for" morphogen" function, yet how Shh instructs distinct digit
identities remains controversial. Here, we bypass the Shh requirement in cell survival during
outgrowth and demonstrate that a transient, early Shh pulse is both necessary and sufficient
for normal mouse limb development. Shh response is only short range and is limited to the
Shh-expressing zone during this time window. Shh patterns digits 1–3, anterior to this zone …
Summary
Limb patterning by Sonic hedgehog (Shh), via either graded spatial or temporal signal integration, is a paradigm for "morphogen" function, yet how Shh instructs distinct digit identities remains controversial. Here, we bypass the Shh requirement in cell survival during outgrowth and demonstrate that a transient, early Shh pulse is both necessary and sufficient for normal mouse limb development. Shh response is only short range and is limited to the Shh-expressing zone during this time window. Shh patterns digits 1–3, anterior to this zone, by an indirect mechanism rather than direct spatial or temporal signal integration. Using a genetic relay-signaling assay, we discover that Shh also specifies digit 1/thumb (thought to be exclusively Shh independent) indirectly, and this finding implicates Shh in a unique regulatory hierarchy for digit 1 evolutionary adaptations such as opposable thumbs. This study illuminates Shh as a trigger for an indirect downstream network that becomes rapidly self-sustaining, with mechanistic relevance for limb development, regeneration, and evolution.
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