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Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [ChIP-seq]

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE134034 | GEO | 2020/05/25

REPOSITORIES: GEO

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Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [RNA-seq]

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

Meis genes regulate RA/FGF signaling to control multiple steps of limb development

Project description:Vertebrate limbs develop by integrating signals that control patterning along three main orthogonal axes. Flank-produced retinoic acid (RA) is initially required for limb induction and establishment of the apical ectodermal ridge (AER), a distal signaling center that produces fibroblast growth factors (FGFs), which are essential for limb growth and distalization. Once the AER is established, RA:FGF antagonism determines the restricted expression of a set of genes that control limb proximodistal patterning. Essential for this antagonism is the activation by FGF of the RA-degrading enzyme CYP26B1 in the distal limb bud. In addition, sonic hedgehog produced from the zone of polarizing activity (ZPA) is essential for distal limb anteroposterior patterning and contributes to RA reduction by cooperating in CYP26B1 activation. Meis transcription factors are expressed in the proximal limb bud, are activated by RA and can regulate proximodistal limb development; however, the mechanisms underlying their activity remain unknown. Here we studied Meis function in the mouse limb bud through Meis2 conditional overexpression and elimination of Meis1 and Meis2. We found that Meis activity is first required for limb bud initiation and the proper establishment of the AER and ZPA signaling centers, and subsequently for the development of proximal limb structures. Functional genomic analyses reveal that Meis is an important conveyor of the RA:FGF antagonism through the regulation of components of the RA and FGF signaling pathways, including CYP26B1. In addition, Meis regulates a set of proximal limb genes controlling proximodistal patterning and differentiation. Our work reveals a regulatory module essential for limb patterning and potentially co-opted in other patterning processes involving RA:FGF antagonism.

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Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis and retinoic acid

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.

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Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in distal forelimb bud

Project description:Suppression of Meis genes in the distal limb bud is required for Proximal-Distal (PD) specification of the forelimb. Polycomb group (PcG) factors play a role in downregulation of retinoic acid (RA)-related signals in the distal forelimb bud, causing Meis repression. It is, however, not known if downregulation of RA-related signals and PcG-mediated proximal genes repression are functionally linked. Here, we reveal that PcG factors and RA-related signals antagonize each other to polarize Meis2 expression along the PD axis. With mathematical modeling and simulation, we propose that PcG factors are required to adjust the threshold for RA-related signaling to regulate Meis2 expression. Finally, we show that a variant Polycomb repressive complex 1 (PRC1), incorporating PCGF3 and PCGF5, represses Meis2 expression in the distal limb bud. Taken together, we reveal a previously unknown link between PcG proteins and downregulation of RA-related signals to mediate the phase transition of Meis2 transcriptional status during forelimb patterning.

2018-09-07 | GSE105206 | GEO

Meis homeobox genes control cell competence within the eye-specified neuroepithelium (ChIP-seq)

Project description:Vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. Eye-specified neuroepithelium forms the optic cup in which spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ) possessing both neurogenic and non-neurogenic potential, and the optic disc (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind the regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence and guardians of spatial territories in the vertebrate eye.

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Meis homeobox genes control cell competence within the eye-specified neuroepithelium (RNA-seq)

2021-02-17 | E-MTAB-9143 | biostudies-arrayexpress

Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors

Project description:Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors

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TALE transcription factors binding and transcriptional effect [RNA-Seq]

Project description:Meis, Prep and Pbx1 TALE homeoproteins interactions with Hox proteins are essential for development and disease. Although Meis and Prep behave similarly in vitro, their in vivo activities remain largely unexplored. We show that Prep and Meis interact with largely independent sets of genomic sites and select different DNA binding sequences, with Prep associating mostly with promoters and house-keeping genes and Meis with promoter-remote regions and developmental genes. Hox target sequences associate strongly with Meis but not with Prep binding sites, while Pbx1 cooperates with both Prep and Meis. Accordingly, Meis1 shows strong genetic interaction with Pbx1 but not with Prep1. Meis1 and Prep1 nonetheless co-regulate a subset of genes, predominantly through opposing effects. Notably, the TALE homeoprotein binding profile subdivides Hox clusters into two domains differentially regulated by Meis1 and Prep1. After duplication of the ancestral gene, Meis and Prep thus specialized their interactions but maintained significant regulatory coordination. RNA-seq of 2 Meis1 and Prep1 loss of function mutants in E11.5 C57BL/6 embryonic mice

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Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [ChIP-seq]

Project description:Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [ChIP-seq]

| PRJNA553525 | ENA

Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [RNA-seq]

Project description:Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [RNA-seq]

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