Roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth.

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Publication Type Journal Article
School or College College of Science; School of Medicine
Department Neurobiology & Anatomy; Oncological Sciences; Human Genetics; Pediatrics; Biology
Program Institute of Human Genetics; Howard Hughes Medical Institute (HHMI)
Creator Moon, Ann M.; Capecchi, Mario R.
Other Author Boulet, Anne M.; Arenkeil, Benjamin R.
Title Roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth.
Date 2004-09
Description Although numerous molecules required for limb bud formation have recently been identified, the molecular pathways that initiate this process and ensure that limb formation occurs at specific axial positions have yet to be fully elucidated. Based on experiments in the chick, Fgf8 expression in the intermediate mesoderm (IM) has been proposed to play a critical role in the initiation of limb bud outgrowth via restriction of Fgf10 expression to the appropriate region of the lateral plate mesoderm. Contrary to the outcome predicted by this model, ablation of Fgf8 expression in the intermediate mesoderm before limb bud initiation had no effect on initial limb bud outgrowth or on the formation of normal limbs. When their expression patterns were first elucidated, both Fgf4 and Fgf8 were proposed to mediate critical functions of the apical ectodermal ridge (AER), which is required for proper limb bud outgrowth. Although mice lacking Fgf4 in the AER have normal limbs, limb development is severely affected in Fgf8 mutants and certain skeletal elements are not produced. By creating mice lacking both Fgf4 and Fgf8 function in the forelimb AER, we show that limb bud mesenchyme fails to survive in the absence of both FGF family members. Thus, Fgf4 is responsible for the partial compensation of distal limb development in the absence of Fgf8. A prolonged period of increased apoptosis, beginning at 10 days of gestation in a proximal-dorsal region of the limb bud, leads to the elimination of enough mesenchymal cells to preclude formation of distal limb structures. Expression of Shh and Fgf10 is nearly abolished in double mutant limb buds. By using a CRE driver expressed in both forelimb and hindlimb ectoderm to inactivate Fgf4 and Fgf8, we have produced mice lacking all limbs, allowing a direct comparison of FGF requirements in the two locations.
Type Text
Publisher Elsevier
Journal Title Developmental Biology
Volume 273
Issue 2
First Page 361
Last Page 372
DOI 10.1016/j.ydbio.2004.06.012
citatation_issn 121606
Subject Animals; Apoptosis; Forelimb; Gene Expression Regulation, Developmental; High Mobility Group Proteins; Hindlimb; In Situ Hybridization; Mesoderm; Mice, Mutant Strains; Trans-Activators
Subject MESH Extremities; Fibroblast Growth Factors; Proto-Oncogene Proteins
Language eng
Bibliographic Citation Dev Biol. 2004 Sep 15;273(2):361-72. Boulet AM, Moon AM; Arenkiel BR; Capecchi MR. The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth.
Rights Management Copyright © 2004 Elsevier. All rights reserved. doi:10.1016/j.ydbio.2004.06.012,
Format Medium application/pdf
Identifier ir-main,566
ARK ark:/87278/s6q81xsn
Setname ir_uspace
Date Created 2012-06-13
Date Modified 2021-05-06
ID 707496
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