|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France
* Present address: Departments of Medicine and Molecular and Cellular Biology, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
These authors contributed equally to this work
Author for correspondence (e-mail: dolle{at}igbmc.u-strasbg.fr)
Accepted 30 April 2002
Numerous studies, often performed on avian embryos, have implicated retinoic acid (RA) in the control of limb bud growth and patterning. Here we have investigated whether the lack of endogenous RA synthesis affects limb morphogenesis in mutant mouse embryos deficient for the retinaldehyde dehydrogenase 2 (Raldh2/Aldh1a2). These mutants, which have no detectable embryonic RA except in the developing retina, die at E9.5-E10 without any evidence of limb bud formation, but maternal RA supplementation through oral gavage from E7.5 can extend their survival. Such survivors exhibit highly reduced forelimb rudiments, but apparently normal hindlimbs. By providing RA within maternal food, we found both a stage- and dose-dependency for rescue of forelimb growth and patterning. Following RA supplementation from E7.5 to 8.5, mutant forelimbs are markedly hypoplastic and lack anteroposterior (AP) patterning, with a single medial cartilage and 1-2 digit rudiments. RA provided until E9.5 significantly rescues forelimb growth, but cannot restore normal AP patterning. Increasing the RA dose rescues the hypodactyly, but leads to lack of asymmetry of the digit pattern, with abnormally long first digit or symmetrical polydactyly. Mutant forelimb buds are characterized by lack of expression or abnormal distal distribution of Sonic hedgehog (Shh) transcripts, sometimes with highest expression anteriorly. Downregulation or ectopic anterior expression of Fgf4 is also seen. As a result, genes such as Bmp2 or Hoxd genes are expressed symmetrically along the AP axis of the forelimb buds, and/or later, of the autopod. We suggest that RA signaling cooperates with a posteriorly restricted factor such as dHand, to generate a functional zone of polarizing activity (ZPA).
Key words: Aldh1a2, dHand, Hox genes, Limb, Mouse development, Raldh2, Retinaldehyde dehydrogenase, Retinoids, Sonic hedgehog
This article has been cited by other articles:
|
|
 |
|
  F. M. J. Jacobs, S. M. Smits, C. W. Noorlander, L. von Oerthel, A. J. A. van der Linden, J. P. H. Burbach, and M. P. Smidt Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency Development, July 15, 2007; 134(14): 2673 - 2684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. L. Sandell, B. W. Sanderson, G. Moiseyev, T. Johnson, A. Mushegian, K. Young, J.-P. Rey, J.-x. Ma, K. Staehling-Hampton, and P. A. Trainor RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development Genes & Dev., May 1, 2007; 21(9): 1113 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Ali-Khan and B. F. Hales Novel Retinoid Targets in the Mouse Limb during Organogenesis Toxicol. Sci., November 1, 2006; 94(1): 139 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Panman, A. Galli, N. Lagarde, O. Michos, G. Soete, A. Zuniga, and R. Zeller Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGF-mediated epithelial-mesenchymal signalling Development, September 1, 2006; 133(17): 3419 - 3428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Gibert, A. Gajewski, A. Meyer, and G. Begemann Induction and prepatterning of the zebrafish pectoral fin bud requires axial retinoic acid signaling Development, July 15, 2006; 133(14): 2649 - 2659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Hoffman, K. Garcha, K. Karamboulas, M. F. Cowan, L. M. Drysdale, W. A. Horton, and T. M. Underhill BMP action in skeletogenesis involves attenuation of retinoid signaling J. Cell Biol., July 3, 2006; 174(1): 101 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Ali-Khan and B. F. Hales Retinoid Receptor Antagonists Alter the Pattern of Apoptosis in Organogenesis Stage Mouse Limbs Toxicol. Sci., March 1, 2006; 90(1): 208 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Ribes, Z. Wang, P. Dolle, and K. Niederreither Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling Development, January 15, 2006; 133(2): 351 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mercader, E. M. Tanaka, and M. Torres Proximodistal identity during vertebrate limb regeneration is regulated by Meis homeodomain proteins Development, September 15, 2005; 132(18): 4131 - 4142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cobb and D. Duboule Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia Development, July 1, 2005; 132(13): 3055 - 3067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Bi, T. Ohyama, H. Nakamura, J. Yan, J. Visvanathan, M. J. Justice, and J. R. Lupski Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome Hum. Mol. Genet., April 15, 2005; 14(8): 983 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Mic, I. O. Sirbu, and G. Duester Retinoic Acid Synthesis Controlled by Raldh2 Is Required Early for Limb Bud Initiation and Then Later as a Proximodistal Signal during Apical Ectodermal Ridge Formation J. Biol. Chem., June 18, 2004; 279(25): 26698 - 26706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lai, B. L. Bohnsack, K. Niederreither, and K. K. Hirschi Retinoic acid regulates endothelial cell proliferation during vasculogenesis Development, December 29, 2003; 130(26): 6465 - 6474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Dupe, N. Matt, J.-M. Garnier, P. Chambon, M. Mark, and N. B. Ghyselinck A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment PNAS, November 25, 2003; 100(24): 14036 - 14041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Mic, A. Molotkov, D. M. Benbrook, and G. Duester Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis PNAS, June 10, 2003; 100(12): 7135 - 7140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Niederreither, J. Vermot, V. Fraulob, P. Chambon, and P. Dolle Retinaldehyde dehydrogenase 2 (RALDH2)- independent patterns of retinoic acid synthesis in the mouse embryo PNAS, December 10, 2002; 99(25): 16111 - 16116. [Abstract] [Full Text] [PDF]
|
|
