Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis and retinoic acid
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ABSTRACT:
PROVIDER: PRJNA610053 | ENA |
REPOSITORIES: ENA
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Project description:Vertebrate axial skeletal patterning is controlled by coordinated collinear expression of Hox genes and axial level-dependent activity of Hox protein combinations. Transcription factors of the Meis family act as cofactors of Hox proteins and profusely bind to Hox complex DNA, however their roles in mammalian axial patterning have not been established. Similarly, retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors, however whether this role is related to Meis/Hox regulation or functions in axial patterning remains unknown. Here we study the role of Meis factors in axial skeleton formation and its relationship to the RA pathway by characterizing Meis1, Meis2 and Raldh2 mutant mice. We report that Meis and Raldh2 regulate each other in a positive feedback regulatory loop that controls axial skeletal identity. Meis elimination produces homeotic transformations similar to those found in Raldh2 and anterior-Hox mutants and disrupts the expression of Hox target genes without changing the transcriptional profiles of Hox complexes. We propose that Meis regulates vertebrate axial skeleton patterning by exclusively affecting Hox protein function, and that alterations in RA levels can produce homeotic transformations without altering Hox transcription through regulating Meis expression.
2020-12-22 | GSE146301 | GEO
Project description:Hox and Cdx transcription factors regulate embryonic positional identities. Cdx mutant mice display posterior body truncations of the axial skeleton, neuraxis, and caudal uro-rectal structures. We show that trunk Hox genes stimulate axial extension as they can largely rescue these Cdx mutant phenotypes. Conversely, posterior (paralog group 13) Hox genes can prematurely arrest posterior axial growth when precociously expressed. Our data suggest that the transition from trunk to tail Hox gene expression successively regulates construction and termination of axial structures in the mouse embryo. Thus, Hox genes seem to differentially orchestrate posterior expansion of embryonic tissues during axial morphogenesis as an integral part of their function in specifying head-to-tail identity. In addition, we present evidence that Cdx and Hox transcription factors exert these effects by controlling Wnt signaling. Concomitant regulation of Cyp26a1 expression, restraining retinoic acid signaling in the posterior growth zone, may likewise play a role in timing the trunk-tail transition.
2009-10-19 | GSE17660 | GEO
Project description:Hox and Cdx transcription factors regulate embryonic positional identities. Cdx mutant mice display posterior body truncations of the axial skeleton, neuraxis, and caudal uro-rectal structures. We show that trunk Hox genes stimulate axial extension as they can largely rescue these Cdx mutant phenotypes. Conversely, posterior (paralog group 13) Hox genes can prematurely arrest posterior axial growth when precociously expressed. Our data suggest that the transition from trunk to tail Hox gene expression successively regulates construction and termination of axial structures in the mouse embryo. Thus, Hox genes seem to differentially orchestrate posterior expansion of embryonic tissues during axial morphogenesis as an integral part of their function in specifying head-to-tail identity. In addition, we present evidence that Cdx and Hox transcription factors exert these effects by controlling Wnt signaling. Concomitant regulation of Cyp26a1 expression, restraining retinoic acid signaling in the posterior growth zone, may likewise play a role in timing the trunk-tail transition.
2009-10-19 | GSE17658 | GEO
Project description:Meis1 and Meis2 are highly similar homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Overexpression experiments have suggested an essential role for Meis factors in limb proximo-distal patterning; however, loss-of-function experiments supporting this notion have not been reported. Meis1 and Meis2 are coexpressed during limb development, first in the lateral plate mesoderm, before limb induction, and then they become restricted to a proximal domain of the growing limb bud. Here, we report that complete double conditional Meis1/2 inactivation in the lateral plate mesoderm leads to limb agenesis. Meis factors cooperate with Tbx factors in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles develop a complete PD set of limb skeletal elements, but show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior skeletal element specification reveals an early role of Meis factors in establishing the limb AP prepattern required for Shh activation at later stages. Our results uncover novel roles for Meis transcription factors in early limb development and identify their involvement in new molecular interaction networks that regulate organogenesis
2020-05-25 | GSE134034 | GEO
Project description:Meis1 and Meis2 are highly similar homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Overexpression experiments have suggested an essential role for Meis factors in limb proximo-distal patterning; however, loss-of-function experiments supporting this notion have not been reported. Meis1 and Meis2 are coexpressed during limb development, first in the lateral plate mesoderm, before limb induction, and then they become restricted to a proximal domain of the growing limb bud. Here, we report that complete double conditional Meis1/2 inactivation in the lateral plate mesoderm leads to limb agenesis. Meis factors cooperate with Tbx factors in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles develop a complete PD set of limb skeletal elements, but show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior skeletal element specification reveals an early role of Meis factors in establishing the limb AP prepattern required for Shh activation at later stages. Our results uncover novel roles for Meis transcription factors in early limb development and identify their involvement in new molecular interaction networks that regulate organogenesis.
2021-03-29 | GSE134039 | GEO
Project description: Not available
| S-EPMC6772169 | biostudies-literature
Project description:The trunk axial skeleton develops from paraxial mesoderm cells. Our recent study demonstrated that conditional knockout of the stem cell factor Sall4 in mice by TCre caused tail truncation and a disorganized axial skeleton posterior to the lumbar level. Based on this phenotype, we hypothesized that, in addition to the previously reported role of Sall4 in neuromesodermal progenitors, Sall4 is involved in the development of the paraxial mesoderm tissue. ATAC-seq in TCre; Sall4 mutant posterior trunk mesoderm shows that Sall4 knockout reduces chromatin accessibility. We found that Sall4- dependent open chromatin status drives activation and repression of WNT signaling activators and repressors, respectively, to promote WNT signaling. Moreover, footprinting analysis of ATAC-seq data suggests that Sall4-dependent chromatin accessibility facilitates CTCF binding, which contributes to the repression of neural genes within the mesoderm. This study unveils multiple mechanisms by which Sall4 regulates paraxial mesoderm development by directing activation of mesodermal genes and repression of neural genes.
2024-02-13 | GSE217671 | GEO
Project description:Meis ChIP-seq on mouse second branchial arch (BA2) and posterior branchial arches connected to outflow tract of the heart (PBA/OFT) at embryonic day (E) 11.5.
2017-09-25 | E-MTAB-5536 | biostudies-arrayexpress
Project description:Meis ChIP-seq on mouse first branchial arch (BA1) and posterior branchial arches connected to outflow tract of the heart (PBA/OFT) at embryonic day (E) 11.5.
2020-01-06 | E-MTAB-7767 | biostudies-arrayexpress
Project description:In vertebrate embryos, anterior tissues are generated early, followed by the other axial structures that emerge sequentially from a posterior growth zone. The genetic network driving posterior axial elongation in mice, and its disturbance in mutants with posterior truncation are not yet fully understood. We show that the combined expression of Cdx2 and T Brachyury is essential to establish the core signature of posterior axial progenitors. Cdx2 and T Brachyury are required for extension of a similar trunk portion of the axis. Simultaneous loss of function of these two genes disrupts axial elongation to a much greater extent than each single mutation alone. We identify and validate common targets for Cdx2 and T Brachyury in vivo including Wnt and Fgf pathway components active in the axial progenitor niche. Our data demonstrate that integration of the Cdx/Hox and T Brachyury transcriptional networks controls differential axial growth during vertebrate trunk elongation.
2016-12-20 | GSE84899 | GEO