Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH.
Correlations between facial anomalies and brain defects are well characterized throughout the clinical literature, yet a developmental basis for this association has not been identified. We demonstrate that the frontonasal process, which gives rise to the mid- and upper face, and the forebrain are linked early in their morphogenesis by a local retinoid signaling event that maintains the expression of key regulatory molecules. First, we show that aldehyde dehydrogenase 6, which synthesizes the ligand, retinoic acid, is localized to the ventral epithelium of the presumptive frontonasal process of chick embryos. At least two retinoid receptors are expressed in adjacent populations of mesenchyme. Second, using synthetic pan-specific retinoid antagonists, we transiently inhibit the ability of retinoid receptors to bind retinoic acid in the rostral head and we generate embryos with a hypoplastic forebrain, fused eyes, and no frontonasal process-derived structures such as the upper beak. These defects are not due to eliminating mesenchymal progenitors, as neural crest cells still migrate into the frontonasal process, despite disruptions to retinoid signaling. Rather, these malformations result from loss of fibroblast growth factor 8 and sonic hedgehog expression, which leads to increased programmed cell death and decreased proliferation in the forebrain and frontonasal process. Most significantly, we can rescue the morphological defects by re-introducing retinoic acid, or fibroblast growth factor and sonic hedgehog proteins into antagonist-treated embryos. We propose that the local source of retinoic acid in the rostral head initiates a regulatory cascade that coordinates forebrain and frontonasal process morphogenesis.
Schneider
R A
RA
Department of Orthopaedic Surgery, 533 Parnassus Avenue, Suite U-453, University of California at San Francisco, San Francisco, CA 94143-0514, USA.
Hu
D
D
Rubenstein
J L
JL
Maden
M
M
Helms
J A
JA
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002642:Chick Embryo; D005145:Face; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D015870:Gene Expression; D053823:Hedgehog Proteins; D009024:Morphogenesis; D009432:Neural Crest / Q000166:cytology; D016548:Prosencephalon / Q000196:embryology*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D047488:Retinoid X Receptors; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta