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Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog.
Dev Biol. 2000 Sep 15; 225(2):392-406.DB

Abstract

The Fgf4 gene encodes an important signaling molecule which is expressed in specific developmental stages, including the inner cell mass of the blastocyst, the myotomes, and the limb bud apical ectodermal ridge (AER). Using a transgenic approach, we previously identified overlapping but distinct enhancer elements in the Fgf4 3' untranslated region necessary and sufficient for myotome and AER expression. Here we have investigated the hypothesis that Fgf4 is a target of myogenic bHLH factors. We show by mutational analysis that a conserved E box located in the Fgf4 myotome enhancer is required for Fgf4-lacZ expression in the myotomes. A DNA probe containing the E box binds MYF5, MYOD, and bHLH-like activities from nuclear extracts of differentiating C2-7 myoblast cells, and both MYF5 and MYOD can activate gene expression of reporter plasmids containing the E-box element. Analyses of Myf5 and MyoD knockout mice harboring Fgf4-lacZ transgenes show that Myf5 is required for Fgf4 expression in the myotomes, while MyoD is not, but MyoD can sustain Fgf4 expression in the ventral myotomes in the absence of Myf5. Sonic hedgehog (Shh) signaling has been shown to have an essential inductive function in the expression of Myf5 and MyoD in the epaxial myotomes, but not in the hypaxial myotomes. We show here that expression of an Fgf4-lacZ transgene in Shh-/- embryos is suppressed not only in the epaxial but also in the hypaxial myotomes, while it is maintained in the AER. This suggests that Shh mediates Fgf4 activation in the myotomes through mechanisms independent of its role in the activation of myogenic factors. Thus, a cascade of events, involving Shh and bHLH factors, is responsible for activating Fgf4 expression in the myotomes in a spatial- and temporal-specific manner.

Authors+Show Affiliations

Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10985858

Citation

Fraidenraich, D, et al. "Activation of Fgf4 Gene Expression in the Myotomes Is Regulated By Myogenic bHLH Factors and By Sonic Hedgehog." Developmental Biology, vol. 225, no. 2, 2000, pp. 392-406.
Fraidenraich D, Iwahori A, Rudnicki M, et al. Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog. Dev Biol. 2000;225(2):392-406.
Fraidenraich, D., Iwahori, A., Rudnicki, M., & Basilico, C. (2000). Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog. Developmental Biology, 225(2), 392-406.
Fraidenraich D, et al. Activation of Fgf4 Gene Expression in the Myotomes Is Regulated By Myogenic bHLH Factors and By Sonic Hedgehog. Dev Biol. 2000 Sep 15;225(2):392-406. PubMed PMID: 10985858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog. AU - Fraidenraich,D, AU - Iwahori,A, AU - Rudnicki,M, AU - Basilico,C, PY - 2000/9/14/pubmed PY - 2000/10/21/medline PY - 2000/9/14/entrez SP - 392 EP - 406 JF - Developmental biology JO - Dev Biol VL - 225 IS - 2 N2 - The Fgf4 gene encodes an important signaling molecule which is expressed in specific developmental stages, including the inner cell mass of the blastocyst, the myotomes, and the limb bud apical ectodermal ridge (AER). Using a transgenic approach, we previously identified overlapping but distinct enhancer elements in the Fgf4 3' untranslated region necessary and sufficient for myotome and AER expression. Here we have investigated the hypothesis that Fgf4 is a target of myogenic bHLH factors. We show by mutational analysis that a conserved E box located in the Fgf4 myotome enhancer is required for Fgf4-lacZ expression in the myotomes. A DNA probe containing the E box binds MYF5, MYOD, and bHLH-like activities from nuclear extracts of differentiating C2-7 myoblast cells, and both MYF5 and MYOD can activate gene expression of reporter plasmids containing the E-box element. Analyses of Myf5 and MyoD knockout mice harboring Fgf4-lacZ transgenes show that Myf5 is required for Fgf4 expression in the myotomes, while MyoD is not, but MyoD can sustain Fgf4 expression in the ventral myotomes in the absence of Myf5. Sonic hedgehog (Shh) signaling has been shown to have an essential inductive function in the expression of Myf5 and MyoD in the epaxial myotomes, but not in the hypaxial myotomes. We show here that expression of an Fgf4-lacZ transgene in Shh-/- embryos is suppressed not only in the epaxial but also in the hypaxial myotomes, while it is maintained in the AER. This suggests that Shh mediates Fgf4 activation in the myotomes through mechanisms independent of its role in the activation of myogenic factors. Thus, a cascade of events, involving Shh and bHLH factors, is responsible for activating Fgf4 expression in the myotomes in a spatial- and temporal-specific manner. SN - 0012-1606 UR - https://www.unboundmedicine.com/medline/citation/10985858/Activation_of_fgf4_gene_expression_in_the_myotomes_is_regulated_by_myogenic_bHLH_factors_and_by_sonic_hedgehog_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(00)99839-7 DB - PRIME DP - Unbound Medicine ER -