Protogenin Facilitates Trunk-to-Tail HOX Code Transition via Modulating GDF11/SMAD2 Signaling in Mammalian Embryos
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE256393 | GEO | 2024/11/13
REPOSITORIES: GEO
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Project description:The axial skeleton of individual mammalian species exhibits remarkable robustness in the number and identity of vertebral elements that form(Owen 1853; Owen 1866; Narita and Kuratani 2005). Between mammalian species however, a great diversity in axial formulae has arisen due to natural selection(Narita and Kuratani 2005; Thewissen et al. 2006; Buchholtz 2007; Matsubara et al. 2017; Kingsley et al. 2017). The genetic mechanism(s) by which axial formulae in mammals is canalised, or manipulated to drive this diversity, remains a major question in biology. Here, we reveal three regulatory pathways essential in constraining total vertebral number and regional axial identity in the mouse. Specifically, the manipulation of Gdf11, Retinoic acid and microRNA-196 activity, individually and cumulatively, led to increasing total vertebral number and allowed us to understand the molecular logic constraining each major division of the vertebral column, from cervical through to tail vertebrae. All three pathways had differing control over Hox cluster expression, with heterochronic and quantitative changes in Hox expression found to parallel changes in axial identity. However, our work revealed an additional, and highly unexpected, role for Hox genes in supporting axial elongation within the tail region. This provides important support for an emerging view that mammalian Hox gene function is not limited to imparting positional identity as the mammalian body plan is laid down, and more broadly, this work provides a molecular framework with which to interrogate mechanisms of evolutionary change.
2023-08-31 | GSE157172 | GEO
Project description:The axial skeleton of individual mammalian species exhibits remarkable robustness in the number and identity of vertebral elements that form(Owen 1853; Owen 1866; Narita and Kuratani 2005). Between mammalian species however, a great diversity in axial formulae has arisen due to natural selection(Narita and Kuratani 2005; Thewissen et al. 2006; Buchholtz 2007; Matsubara et al. 2017; Kingsley et al. 2017). The genetic mechanism(s) by which axial formulae in mammals is canalised, or manipulated to drive this diversity, remains a major question in biology. Here, we reveal three regulatory pathways essential in constraining total vertebral number and regional axial identity in the mouse. Specifically, the manipulation of Gdf11, Retinoic acid and microRNA-196 activity, individually and cumulatively, led to increasing total vertebral number and allowed us to understand the molecular logic constraining each major division of the vertebral column, from cervical through to tail vertebrae. All three pathways had differing control over Hox cluster expression, with heterochronic and quantitative changes in Hox expression found to parallel changes in axial identity. However, our work revealed an additional, and highly unexpected, role for Hox genes in supporting axial elongation within the tail region. This provides important support for an emerging view that mammalian Hox gene function is not limited to imparting positional identity as the mammalian body plan is laid down, and more broadly, this work provides a molecular framework with which to interrogate mechanisms of evolutionary change.
2023-08-31 | GSE157171 | GEO
Project description:The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. For the vertebral column, the process of axial progenitor cell expansion that drives axis elongation, and the process of segmentation which allocates these progenitors into repeating vertebral units, occurs seemingly uninterrupted from the first to the last vertebra. Nonetheless, there is clear developmental and evolutionary support for two discrete modules controlling processes within different axial regions: a trunk module and a tail module. The secreted signal Gdf11 has been identified as a principal regulator of timing the trunk-to-tail (T-to-T) transition, but has pleiotropic effects across much of the main body axis, highlighting the need to reveal intrinsic regulatory networks that function to exclusively control one or the other module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analysis revealed that the precise level of Nr6a1 acts as a rheostat, expanding or contracting vertebral number of the trunk region autonomously from other axial regions. Moreover, the timely clearance of Nr6a1 observed at the T-to-T transition was essential in allowing the tail module to operate correctly. In parallel with these effects on vertebral number, we show that Nr6a1 controls the timely progression of global Hox signatures within axial progenitors, preventing the precocious expression of multiple posterior Hox genes as the trunk is being laid down and thus reinforcing that patterning and elongation are coordinated. Finally, our data supports a crucial role for Nr6a1 in regulating gene regulatory networks that guide cell lineage choice of axial progenitors between neural and mesodermal fate. Collectively, our data reveals an axially-restricted role for Nr6a1 in all major cellular and tissue-level events required for vertebral column formation, supporting the view that modulation of Nr6a1 expression level or function may underpin evolutionary changes in axial formulae that exclusively alter the trunk region.
2023-01-03 | GSE180426 | GEO
Project description:The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. For the vertebral column, the process of axial progenitor cell expansion that drives axis elongation, and the process of segmentation which allocates these progenitors into repeating vertebral units, occurs seemingly uninterrupted from the first to the last vertebra. Nonetheless, there is clear developmental and evolutionary support for two discrete modules controlling processes within different axial regions: a trunk module and a tail module. The secreted signal Gdf11 has been identified as a principal regulator of timing the trunk-to-tail (T-to-T) transition, but has pleiotropic effects across much of the main body axis, highlighting the need to reveal intrinsic regulatory networks that function to exclusively control one or the other module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analysis revealed that the precise level of Nr6a1 acts as a rheostat, expanding or contracting vertebral number of the trunk region autonomously from other axial regions. Moreover, the timely clearance of Nr6a1 observed at the T-to-T transition was essential in allowing the tail module to operate correctly. In parallel with these effects on vertebral number, we show that Nr6a1 controls the timely progression of global Hox signatures within axial progenitors, preventing the precocious expression of multiple posterior Hox genes as the trunk is being laid down and thus reinforcing that patterning and elongation are coordinated. Finally, our data supports a crucial role for Nr6a1 in regulating gene regulatory networks that guide cell lineage choice of axial progenitors between neural and mesodermal fate. Collectively, our data reveals an axially-restricted role for Nr6a1 in all major cellular and tissue-level events required for vertebral column formation, supporting the view that modulation of Nr6a1 expression level or function may underpin evolutionary changes in axial formulae that exclusively alter the trunk region.
2023-01-03 | GSE179858 | GEO
Project description:We have identified an ENU-induced recessive mouse mutation (Vcc) with a pleiotropic phenotype overlapping including cardiac, tracheo-esophageal, anorectal, axial skeletal antero-posterior patterning defects, limb malformations, presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. It results from a C470R mutation in the proprotein convertase PCSK5 (PC5/6, SPC6) that fails to complement a null allele, which also has a similar phenotype. The mutation ablates a predicted disulfide bond in the P domain, and results in reduced secretion, abnormal cellular localisation, and loss of proprotein convertase activity. We analysed whole genome gene expression in a mouse line carrying ENU-generated point mutation in Pcsk5 gene on a mixed background : 25% C57BL6/J on C3H/HeH (mutation originally introduced into C57BL6/J). We show that GDF11, a regulator of Hox expression, anteroposterior patterning and nephrogenesis, is a PCSK5 target, and that Pcsk5 mutation results in abnormal expression of several paralogous caudal Hox genes (Hoxa, Hoxc, Hoxd), and Mnx1 (Hlxb9) that are necessary for caudal embryo development. Our data establishes novel and pleiotropic functions for Pcsk5 in mammalian development and the coordinated expression of caudal Hox genes; and identifies GDF11 as a novel cleavage target for PCSK5. We propose that Pcsk5, at least in part via GDF11, coordinately regulates the expression of caudal Hox paralogs, to control antero-posterior patterning, nephrogenesis, and skeletal and anorectal development.
2008-06-27 | E-TABM-443 | biostudies-arrayexpress
Project description:Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether HOX genes sequential activation, the “HOX clock”, is paced by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cells differentiating into spinal cord motor neuron subtypes which are progenies of axial progenitors. We show that the progressive activation of caudal HOX genes is controlled by a dynamic increase in FGF signaling. Blocking FGF pathway stalled induction of HOX genes, while precocious increase in FGF alone, or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The HOX clock is thus dynamically paced by exposure parameters to secreted cues. Its manipulation by extrinsic factors alleviates temporal requirements to provide unprecedented synchronized access to human cells of multiple, defined, rostro-caudal identities for basic and translational applications.
2021-03-02 | GSE153519 | 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: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. Experiment Overall Design: A micro-array screen of down regulated and upregulated genes in Cdx2+/-Cdx4-/- mutant embryos versus wildtype embryos was performed at the embryonic stage of 13 somites. RNA was isolated from the posterior part of the embryos dissected at the same axial level using the last somite boundary as a landmark. Posterior tissues from pools of 7 embryos of each genotype were pooled. The labeled cRNAs were hybridized on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in a dye swap experiment, resulting in two individual microarrays.
2009-10-23 | E-GEOD-17660 | biostudies-arrayexpress
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. Experiment Overall Design: A micro-array screen of down regulated and upregulated genes in Cdx2+/-Cdx4-/- mutant embryos versus wildtype embryos was performed at the embryonic stage of 5/6 somites. RNA was isolated from the posterior part of the embryos dissected at the same axial level using the last somite boundary as a landmark. Posterior tissues from pools of 10 embryos of each genotype were pooled. The labeled cRNAs were hybridized on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments, resulting in four individual microarrays.
2009-10-23 | E-GEOD-17658 | biostudies-arrayexpress