Abstract
Background: Retinoic acid is implicated in the induction of the gene encoding Sonic hedgehog (Shh) that specifies anteroposterior positional values and promotes growth of the developing limb bud. However, because retinoic acid is involved in limb initiation, it has been difficult to determine if it could have additional roles in anteroposterior patterning. To investigate this, we implanted retinoic acid–soaked beads to the anterior margin of the chick wing bud and performed microarray analyses prior to onset of Shh expression. Results: Retinoic acid up‐regulates expression of Hoxd11‐13 that encode transcription factors implicated in inducing Shh transcription and that are involved in digit development. In our assay, retinoic acid induces Shh transcription and, consequently, a new pattern of digits at a much later stage than anticipated. Retinoic acid represses many anteriorly expressed genes, including Bmp4, Lhx9, Msx2, and Alx4. We provide evidence that retinoic acid influences transcription via induction of dHAND and inhibition of Gli3 to establish a new anteroposterior pre‐pattern. We show that transient exposure to retinoic acid can suppress distal development and expedite cells to transcriptionally respond to Shh. Conclusions: Our findings reveal how retinoic acid and Shh signaling could cooperate in anteroposterior patterning of the limb. Developmental Dynamics 246:682–690, 2017. © 2017 Wiley Periodicals, Inc.
Highlights
One of the earliest discovered effects of retinoic acid signaling on limb development was in influencing patterning along the anteroposterior axis of the chick wing (Tickle et al, 1982)
We have further examined how retinoic acid signaling could influence anteroposterior patterning by implanting retinoic acid–soaked beads to the anterior margin of the chick wing bud under conditions in which ectopic Sonic hedgehog (Shh) is not induced until late bud stages
We have shown that the application of retinoic acid to the anterior margin of the HH20 chick wing bud can induce a new pattern of digits after HH26 in a Shh-dependent manner, a much later stage than anticipated
Summary
One of the earliest discovered effects of retinoic acid signaling on limb development was in influencing patterning along the anteroposterior axis (thumb to little finger) of the chick wing (Tickle et al, 1982). Such duplicated digit patterns are similar to those obtained when a specialized group of posterior mesenchyme cells—known as the polarizing region—are grafted to the anterior margins of host wing buds (Saunders and Gasseling, 1968) Based on these observations, it was suggested that retinoic acid could be the sought after morphogen produced by the polarizing region that specifies cells with positional values across the anteroposterior axis in a concentration-dependent manner (Wolpert, 1969; Tickle et al., 1975). It was later shown that retinoic acid induces a new polarizing region (Noji et al, 1991; Wanek et al, 1991) and that its effects on specifying a new pattern of digits are mediated by the secreted peptide encoded by the Sonic hedgehog (Shh) gene (Riddle et al, 1993; Helms et al, 1994) It is not clear if retinoic acid is involved in the initiation of Shh expression in normal limb development. VC 2017 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists
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