Abstract
BackgroundGlobal analyses of gene expression during development reveal specific transcription patterns associated with the emergence of various cell types, tissues, and organs. These heterogeneous patterns are instrumental to ensure the proper formation of the different parts of our body, as shown by the phenotypic effects generated by functional genetic approaches. However, variations at the cellular level can be observed within each structure or organ. In the developing mammalian limbs, expression of Hox genes from the HoxD cluster is differentially controlled in space and time, in cells that will pattern the digits and the forearms. While the Hoxd genes broadly share a common regulatory landscape and large-scale analyses have suggested a homogenous Hox gene transcriptional program, it has not previously been clear whether Hoxd genes are expressed together at the same levels in the same cells.ResultsWe report a high degree of heterogeneity in the expression of the Hoxd11 and Hoxd13 genes. We analyzed single-limb bud cell transcriptomes and show that Hox genes are expressed in specific combinations that appear to match particular cell types. In cells giving rise to digits, we find that the expression of the five relevant Hoxd genes (Hoxd9 to Hoxd13) is unbalanced, despite their control by known global enhancers. We also report that specific combinatorial expression follows a pseudo-time sequence, which is established based on the transcriptional diversity of limb progenitors.ConclusionsOur observations reveal the existence of distinct combinations of Hoxd genes at the single-cell level during limb development. In addition, we document that the increasing combinatorial expression of Hoxd genes in this developing structure is associated with specific transcriptional signatures and that these signatures illustrate a temporal progression in the differentiation of these cells.
Highlights
Global analyses of gene expression during development reveal specific transcription patterns associated with the emergence of various cell types, tissues, and organs
We observed a high expression specificity in presumptive digit cells in the distal part of the forelimb, with the highest transcript levels in cells located at the boundary between the digital and the interdigital compartments, while lower levels were scored in interdigital mesenchyme
The single-cell preparation was analyzed by fluorescence-activated cell sorting (FACS) and revealed that only a minority of cells was expressing Hoxd11 and/or Hoxd13 (Fig. 1c)
Summary
Global analyses of gene expression during development reveal specific transcription patterns associated with the emergence of various cell types, tissues, and organs. These heterogeneous patterns are instrumental to ensure the proper formation of the different parts of our body, as shown by the phenotypic effects generated by functional genetic approaches. In the developing mammalian limbs, expression of Hox genes from the HoxD cluster is differentially controlled in space and time, in cells that will pattern the digits and the forearms. The posterior Hoxd genes are expressed in precise, partly overlapping domains [1], which will pre-figure the various parts of the future appendices, i.e., the hands and feet (autopods) and the more proximally located arm (stylopod) and forearm (zeugopod) segments.
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