Abstract
Detailed information about stage-specific changes in gene expression is crucial for understanding the gene regulatory networks underlying development and the various signal transduction pathways contributing to morphogenesis. Here we describe the global gene expression dynamics during early murine limb development, when cartilage, tendons, muscle, joints, vasculature and nerves are specified and the musculoskeletal system of limbs is established. We used whole-genome microarrays to identify genes with differential expression at 5 stages of limb development (E9.5 to 13.5), during fore- and hind-limb patterning. We found that the onset of limb formation is characterized by an up-regulation of transcription factors, which is followed by a massive activation of genes during E10.5 and E11.5 which levels off at later time points. Among the 3520 genes identified as significantly up-regulated in the limb, we find ∼30% to be novel, dramatically expanding the repertoire of candidate genes likely to function in the limb. Hierarchical and stage-specific clustering identified expression profiles that are likely to correlate with functional programs during limb development and further characterization of these transcripts will provide new insights into specific tissue patterning processes. Here, we provide for the first time a comprehensive analysis of developmentally regulated genes during murine limb development, and provide some novel insights into the expression dynamics governing limb morphogenesis.
Highlights
The developing limb serves as an ideal model for studying differentiation of pluripotent mesenchymal cells into several distinct tissues, including cartilage, muscle, blood vessels, tendons and endochondral bone [1]
To identify novel molecules responsible for limb patterning processes and determinants of limb identity, as well as to characterize the expression profiles of genes co-transcribed at high levels during limb development, we generated mouse wholegenome microarray gene expression data for fore- and hind-limbs from five consecutive developmental time points, from E9.5 to E13.5 (Figure 1), accompanied by data for whole embryos as controls
This analysis provides a detailed description of the gene expression dynamics during murine limb development from limb bud initiation at E9.5 to a fully patterned autopod, at E13.5, and complements other efforts that attempt to study individual genes and pathways during limb morphogenesis through gene visualization or targeted mutagenesis
Summary
The developing limb serves as an ideal model for studying differentiation of pluripotent mesenchymal cells into several distinct tissues, including cartilage, muscle, blood vessels, tendons and endochondral bone [1]. While the limb is a well established model system for studying genetic factors that regulate tissue patterning, differentiation and growth, the last decade of limb development research has been dominated by the same collection of widely studied genes, with little introduction of new candidate contributors. There are about 221 syndromes described with polydactyly and 120 syndromes with oligodactyly [2] Despite this wide prevalence of limb abnormalities, to date only ,84 genes have been associated with syndromes that include limb defects, 15 of which have described polydactyly [2]. We have yet to grasp how the genome specifies fore- and hind-limb patterning to establish limb identity and result in the formation of complex homologous structures that are distinct in shape and function, such as the human hand and foot [4,5]
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