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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #308147
Title: A switch from low to high Shh activity regulates establishment of limb progenitors and signaling centers

Author
item ZHULYN, OLENA - Hospital For Sick Children (SICKKIDS)
item LI, DANYI - Hospital For Sick Children (SICKKIDS)
item DEIMLING, STEVEN - Hospital For Sick Children (SICKKIDS)
item VAKILI, NIKI ALIZADEH - Hospital For Sick Children (SICKKIDS)
item MO, RONG - Hospital For Sick Children (SICKKIDS)
item PUVIINDRAN, VIJITHA - Hospital For Sick Children (SICKKIDS)
item CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC)
item CHUANG, PAO-TIEN - University Of California
item HOPYAN, SEVAN - Hospital For Sick Children (SICKKIDS)
item HUI, CHI-CHUNG - Hospital For Sick Children (SICKKIDS)

Submitted to: Developmental Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2014
Publication Date: 4/10/2014
Citation: Zhulyn, O., Li, D., Deimling, S., Vakili, N., Mo, R., Puviindran, V., Chen, M., Chuang, P., Hopyan, S., Hui, C. 2014. A switch from low to high Shh activity regulates establishment of limb progenitors and signaling centers. Developmental Cell. 29(2):241-249.

Interpretive Summary: The Hedgehog signaling pathway controls the number and growth of fingers and toes during development. In this paper, we show that mice develop extra fingers and toes when Hedgehog signaling is activated before normal limb patterning begins in the developing embryo. Because mutations in human Hedgehog pathway components often result in birth defects, including polydactyl (extra toes), the knowledge obtained from this study will help us understand the causes of these birth defects in humans.

Technical Abstract: The patterning and growth of the embryonic vertebrate limb is dependent on Sonic hedgehog (Shh), a morphogen that regulates the activity of Gli transcription factors. However, "Shh" expression is not observed during the first 12 hours of limb development. During this phase, the limb bud is prepatterned into anterior and posterior regions through the antagonistic actions of transcription factors "Gli3" and "Hand2". We demonstrate that precocious activation of Shh signaling during this early phase interferes with the Gli3-dependent specification of anterior progenitors, disturbing establishment of signaling centers and normal outgrowth of the limb. Our findings illustrate that limb development requires a sweet spot in the level and timing of pathway activation that allows for the Shh-dependent expansion of posterior progenitors without interfering with early prepatterning functions of "Gli3"/Gli3R or specification of anterior progenitors.