The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures

  1. Suzan Abu-Abed1,3,
  2. Pascal Dollé2,3,
  3. Daniel Metzger2,
  4. Barbara Beckett1,
  5. Pierre Chambon2, and
  6. Martin Petkovich1,4
  1. 1Cancer Research Labs, Queen's University, Kingston, Ontario, K7L 3N6, Canada; 2Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 163-67404 Illkirch Cedex, CU de Strasbourg, France

Abstract

The active derivative of vitamin A, retinoic acid (RA), is essential for normal embryonic development. The spatio-temporal distribution of embryonic RA results from regulated expression of RA-synthesizing retinaldehyde dehydrogenases and RA-metabolizing cytochrome P450s (CYP26). Excess RA administration or RA deficiency results in a complex spectrum of embryonic abnormalities. As a first step in understanding the developmental function of RA-metabolizing enzymes, we have disrupted the murine Cyp26A1 gene. We report thatCyp26A1-null mutants die during mid-late gestation and show a number of major morphogenetic defects. Spina bifida and truncation of the tail and lumbosacral region (including abnormalities of the kidneys, urogenital tract, and hindgut) are the most conspicuous defects, leading in extreme cases to a sirenomelia (“mermaid tail”) phenotype. Cyp26A1 mutants also show posterior transformations of cervical vertebrae and abnormal patterning of the rostral hindbrain, which appears to be partially posteriorly transformed. These defects correlate with two major sites of Cyp26A1 expression in the rostral neural plate and embryonic tail bud. Because all of theCyp26A1 −/− abnormalities closely resemble RA teratogenic effects, we postulate that the key function of CYP26A1 is to maintain specific embryonic areas in a RA-depleted state, to protect them against the deleterious effect of ectopic RA signaling.

Keywords

Footnotes

  • 3 These authors contributed equally to this work.

  • 4 Corresponding author.

  • E-MAIL petkovic{at}post.queensu.ca; FAX (613) 533-6830.

  • Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.855001.

    • Received September 27, 2000.
    • Accepted December 6, 2000.
| Table of Contents

Life Science Alliance