Dataset Information

Cux2 refines the forelimb field by controlling expression of Raldh2 and Hox genes.

ABSTRACT: In vertebrates, two pairs of buds that give rise to the fore- and hindlimbs form at discrete positions along the rostral-caudal axis of the body. The mechanism responsible for the positioning of the limb buds is still largely unknown. Here we show a novel function for Cut homeobox transcription factor 2 (Cux2), the ortholog of Drosophila cut, in refining the forelimb field during chick development. Cux2 is expressed in the forelimb field before the emergence of the limb buds. Knocking down the expression of Cux2 using small interfering RNA (siRNA) resulted in a caudal shift of the forelimb bud, whereas misexpression of Cux2 or the constitutively active Cux2-VP16 caused a rostral shift of the forelimb bud or reduction of the forelimb field along the anterior-posterior axis. Further functional analyses revealed that expression of Hoxb genes and retinaldehyde dehydrogenase 2 (Raldh2), which are involved in limb positioning, are directly activated by Cux2 in the lateral plate mesoderm. Our data suggest that Cux2 in the lateral plate mesoderm refines the forelimb field via regulation of Raldh2 and Hoxb genes in chicken embryos.

SUBMITTER: Ueda S

PROVIDER: S-EPMC6398465 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Cux2 refines the forelimb field by controlling expression of Raldh2 and Hox genes.

Ueda Shogo S Cordeiro Ingrid Rosenburg IR Moriyama Yuuta Y Nishimori Chika C Kai Kei-Ichi KI Yu Reiko R Nakato Ryoichiro R Shirahige Katsuhiko K Tanaka Mikiko M

Biology open 20190201 2

In vertebrates, two pairs of buds that give rise to the fore- and hindlimbs form at discrete positions along the rostral-caudal axis of the body. The mechanism responsible for the positioning of the limb buds is still largely unknown. Here we show a novel function for Cut homeobox transcription factor 2 (Cux2), the ortholog of Drosophila cut, in refining the forelimb field during chick development. Cux2 is expressed in the forelimb field before the emergence of the limb buds. Knock ...[more]

PMID: 30651234

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Project description:Tight control over gene expression is essential for precision in embryonic development and acquisition of the regulatory elements responsible is the predominant driver for evolution of new structures. Tbx5 and Tbx4, two genes expressed in forelimb and hindlimb-forming regions respectively, play crucial roles in the initiation of limb outgrowth. Evolution of regulatory elements that activate Tbx5 in rostral LPM was essential for the acquisition of forelimbs in vertebrates. We identified such a regulatory element for Tbx5 and demonstrated Hox genes are essential, direct regulators. While the importance of Hox genes in regulating embryonic development is clear, Hox targets and the ways in which each protein executes its specific function are not known. We reveal how nested Hox expression along the rostro-caudal axis restricts Tbx5 expression to forelimb. We demonstrate that Hoxc9, which is expressed in caudal LPM where Tbx5 is not expressed, can form a repressive complex on the Tbx5 forelimb regulatory element. This repressive capacity is limited to Hox proteins expressed in caudal LPM and carried out by two separate protein domains in Hoxc9. Forelimb-restricted expression of Tbx5 and ultimately forelimb formation is therefore achieved through co-option of two characteristics of Hox genes; their colinear expression along the body axis and the functional specificity of different paralogs. Active complexes can be formed by Hox PG proteins present throughout the rostral-caudal LPM while restriction of Tbx5 expression is achieved by superimposing a dominant repressive (Hoxc9) complex that determines the caudal boundary of Tbx5 expression. Our results reveal the regulatory mechanism that ensures emergence of the forelimbs at the correct position along the body. Acquisition of this regulatory element would have been critical for the evolution of limbs in vertebrates and modulation of the factors we have identified can be molecular drivers of the diversity in limb morphology.

Project description:IntroductionOnychophora is a relatively small phylum within Ecdysozoa, and is considered to be the sister group to Arthropoda. Compared to the arthropods, that have radiated into countless divergent forms, the onychophoran body plan is overall comparably simple and does not display much in-phylum variation. An important component of arthropod morphological diversity consists of variation of tagmosis, i.e. the grouping of segments into functional units (tagmata), and this in turn is correlated with differences in expression patterns of the Hox genes. How these genes are expressed in the simpler onychophorans, the subject of this paper, would therefore be of interest in understanding their subsequent evolution in the arthropods, especially if an argument can be made for the onychophoran system broadly reflecting the ancestral state in the arthropods.ResultsThe sequences and embryonic expression patterns of the complete set of ten Hox genes of an onychophoran (Euperipatoides kanangrensis) are described for the first time. We find that they are all expressed in characteristic patterns that suggest a function as classical Hox genes. The onychophoran Hox genes obey spatial colinearity, and with the exception of Ultrabithorax (Ubx), they all have different and distinct anterior expression borders. Notably, Ubx transcripts form a posterior to anterior gradient in the onychophoran trunk. Expression of all onychophoran Hox genes extends continuously from their anterior border to the rear end of the embryo.ConclusionsThe spatial expression pattern of the onychophoran Hox genes may contribute to a combinatorial Hox code that is involved in giving each segment its identity. This patterning of segments in the uniform trunk, however, apparently predates the evolution of distinct segmental differences in external morphology seen in arthropods. The gradient-like expression of Ubx may give posterior segments their specific identity, even though they otherwise express the same set of Hox genes. We suggest that the confined domains of Hox gene expression seen in arthropods evolved from an ancestral onychophoran-like Hox gene pattern. Reconstruction of the ancestral arthropod Hox pattern and comparison with the patterns in the different arthropod classes reveals phylogenetic support for Mandibulata and Tetraconata, but not Myriochelata and Atelocerata.

Dataset Information

Cux2 refines the forelimb field by controlling expression of Raldh2 and Hox genes.

Publications

Cux2 refines the forelimb field by controlling expression of <i>Raldh2</i> and <i>Hox</i> genes.

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