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First published online December 12, 2006
doi: 10.1242/10.1242/dev.02706

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Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

Rafael E. Hernandez^1,2,*, Aaron P. Putzke^1,*, Jonathan P. Myers^1,, Lilyana Margaretha¹ and Cecilia B. Moens^1,

¹ HHMI and Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109-1024, USA.
² Medical Scientist Training Program and Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195-7470, USA.

Author for correspondence (e-mail: cmoens{at}fhcrc.org)

Accepted 18 October 2006

Retinoic acid (RA) is essential for normal vertebrate development, including the patterning of the central nervous system. During early embryogenesis, RA is produced in the trunk mesoderm through the metabolism of vitamin A derived from the maternal diet and behaves as a morphogen in the developing hindbrain where it specifies nested domains of Hox gene expression. The loss of endogenous sources of RA can be rescued by treatment with a uniform concentration of exogenous RA, indicating that domains of RA responsiveness can be shaped by mechanisms other than the simple diffusion of RA from a localized posterior source. Here, we show that the cytochrome p450 enzymes of the Cyp26 class, which metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development. In zebrafish embryos depleted of the orthologs of the three mammalian CYP26 genes CYP26A1, CYP26B1 and CYP26C1, the entire hindbrain expresses RA-responsive genes that are normally restricted to nested domains in the posterior hindbrain. Furthermore, we show that Cyp26 enzymes are essential for exogenous RA to rescue hindbrain patterning in RA-depleted embryos. We present a `gradient-free' model for hindbrain patterning in which differential RA responsiveness along the hindbrain anterior-posterior axis is shaped primarily by the dynamic expression of RA-degrading enzymes.

Key words: Retinoic acid, Hindbrain, Cyp26, Hox, Morphogen, Zebrafish

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Degrading uniformity in hindbrain patterning

Development 2007 134: e102. [Full Text]  

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