title: Inhibition of retinoic acid receptor-mediated signalling alters positional identity in the developing hindbrain.
abstract: Retinoids regulate gene expression via nuclear retinoic acid receptors, the RARs and RXRs. To investigate the functions of retinoid receptors during early neural development, we expressed a dominant negative RARbeta in early Xenopus embryos. We obtained evidence that dominant negative RARbeta specifically inhibits RAR/RXR heterodimer-mediated, but not RXR homodimer-mediated, transactivation. Both all-trans- and 9-cis-RA-induced teratogenesis were, however, efficiently opposed by ectopic expression of dominant negative RARbeta, indicating that only RAR/RXR transactivation is required for retinoid teratogenesis by each of these ligands. Experiments with two RXR-selective ligands confirmed that activation of RXR homodimers does not cause retinoid teratogenesis. Dominant negative RARbeta thus specifically interferes with the retinoid signalling pathway that is responsible for retinoid teratogenesis. Dominant negative RARbeta-expressing embryos had a specific developmental phenotype leading to disorganization of the hindbrain. Mauthner cell multiplications in the posterior hindbrain, and (both anteriorly and posteriorly) expanded Krox-20 expression domains indicated (partial) transformation of a large part of the hindbrain into (at least partial) rhombomere 3, 4 and/or 5 identity. In contrast, the fore- and midbrain and spinal cord appeared to be less affected. These data indicate that RARs play a role in patterning the hindbrain.
authors.affiliation: Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
authors.forename: J
authors.initials: J
authors.lastname: van der Wees
authors.forename: J G
authors.initials: JG
authors.lastname: Schilthuis
authors.forename: C H
authors.initials: CH
authors.lastname: Koster
authors.forename: H
authors.initials: H
authors.lastname: Diesveld-Schipper
authors.forename: G E
authors.initials: GE
authors.lastname: Folkers
authors.forename: P T
authors.initials: PT
authors.lastname: van der Saag
authors.forename: M I
authors.initials: MI
authors.lastname: Dawson
authors.forename: K
authors.initials: K
authors.lastname: Shudo
authors.forename: B
authors.initials: B
authors.lastname: van der Burg
authors.forename: A J
authors.initials: AJ
authors.lastname: Durston
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D019281:Dimerization; D051767:Early Growth Response Protein 2; D015870:Gene Expression; D005799:Genes, Dominant; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047488:Retinoid X Receptors; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology*; D015398:Signal Transduction / Q000502:physiology*; D013723:Teratogens / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D014981:Xenopus
chemical_list: D004268:DNA-Binding Proteins; C497329:EGR2 protein, Xenopus; D051767:Early Growth Response Protein 2; D008024:Ligands; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013723:Teratogens; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D000077556:Alitretinoin; D014212:Tretinoin