Dataset Information

Fgf4 maintains Hes7 levels critical for normal somite segmentation clock function.

ABSTRACT: During vertebrate development, the presomitic mesoderm (PSM) periodically segments into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. Here, we examined mouse mutants lacking only Fgf4 or Fgf8, which we previously demonstrated act redundantly to prevent PSM differentiation. Fgf8 is not required for somitogenesis, but Fgf4 mutants display a range of vertebral defects. We analyzed Fgf4 mutants by quantifying mRNAs fluorescently labeled by hybridization chain reaction within Imaris-based volumetric tissue subsets. These data indicate that FGF4 maintains Hes7 levels and normal oscillatory patterns. To support our hypothesis that FGF4 regulates somitogenesis through Hes7, we demonstrate genetic synergy between Hes7 and Fgf4, but not with Fgf8. Our data indicate that Fgf4 is potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations.

SUBMITTER: Anderson MJ

PROVIDER: S-EPMC7717904 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fgf4 maintains Hes7 levels critical for normal somite segmentation clock function.

Anderson Matthew J MJ Magidson Valentin V Kageyama Ryoichiro R Lewandoski Mark M

eLife 20201119

During vertebrate development, the presomitic mesoderm (PSM) periodically segments into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. Here, we examined mouse mutants lacking only Fgf4 or Fgf8, which we previously demonstrated act redundantly to prevent PSM differentiation. Fgf8 is not required for somitogenesis, ...[more]

PMID: 33210601

Similar Datasets

Project description:The reduced cost and improved efficiency of whole genome sequencing (WGS) is drastically improving the development of cats as biomedical models. Persian cats are models for Leber's congenital amaurosis (LCA), the most severe and earliest onset form of visual impairment in humans. Cats with innocuous breed-defining traits, such as a bobbed tail, can also be models for somite segmentation and vertebral column development.The first WGS in cats was conducted on a trio segregating for LCA and the bobbed tail abnormality. Variants were identified using FreeBayes and effects predicted using SnpEff. Variants within a known haplotype block for cat LCA and specific candidate genes for both phenotypes were prioritized by the predicted variant effect on the proteins and concordant segregation within the trio. The efficiency of WGS of a single trio of domestic cats was evaluated.A stop gain was identified at position c.577C > T in cat AIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified in HES7. The variants segregated concordantly in a Persian - Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for the AIPL1 variant, defining an allelic frequency in only Persian -related breeds of 1.15%. A sub-set of cats was genotyped for the HES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The cat AIPL1 variant would have been considered a high priority variant for evaluation, regardless of a priori knowledge from previous genetic studies.This study represents the first effort of the 99 Lives Cat Genome Sequencing Initiative to identify disease--causing variants in the domestic cat using WGS. The current cat reference assembly is efficient for gene and variant identification. However, as the feline variant database improves, development of cats as biomedical models for human disease will be more efficient, providing an alternative, large animal model for drug and gene therapy trials. Undiagnosed human patients with early-onset blindness should be screened for this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.

Project description:Pluripotent stem cells (PSCs) have increasingly been used to model different aspects of embryogenesis and organ formation. Despite recent advances in the in vitro induction of major mesodermal lineages and mesoderm-derived cell types experimental model systems that can recapitulate more complex biological features of human mesoderm development and patterning are largely missing. Here, we utilized induced pluripotent stem cells (iPSCs) for the stepwise in vitro induction of presomitic mesoderm (PSM) and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modeling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We succeeded to observe oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours and showed the presence of dynamic traveling wave-like gene expression within in vitro induced human PSM. We furthermore identified and compared oscillatory genes in human and murine PSC-derived PSM, which revealed species-specific as well as common molecular components and novel pathways associated with the mouse and human segmentation clocks. Utilizing CRISPR/Cas9-based genome editing technology, we then targeted genes, for which mutations in patients with segmentation defects of vertebrae (SDV) such as spondylocostal dysostosis (SCD) have been reported (e.g. HES7, LFNG, DLL3 and MESP2 DLL3). Subsequent analysis of patient-like knock-out and point-mutation lines as well as patient-derived iPSCs together with their genetically corrected isogenic controls revealed gene-specific alterations in oscillation, synchronization or differentiation properties, validating the overall utility of our model system, to provide novel insights into the human segmentation clock as well as diseases associated with the formation of the human axial skeleton.

Dataset Information

Fgf4 maintains Hes7 levels critical for normal somite segmentation clock function.

Publications

<i>Fgf4</i> maintains <i>Hes7</i> levels critical for normal somite segmentation clock function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets