Microrna-455 in cartilage and skeletal development

Paddy, Paige (2021) Microrna-455 in cartilage and skeletal development. Doctoral thesis, University of East Anglia.

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microRNAs (miRNAs) are a family of short endogenous non-coding RNAs with a sequence length of 19 to 23 nucleotides, functioning as post-transcriptional regulators of gene expression. During skeletal development, several miRNAs have been identified as important regulators of osteochondral genes. For example, miR-455 is located in an intron of the COL27A1 gene and has been implicated in cartilage physiology and pathology. The aim of this research was to define a role for miR-455-3p in cartilage and skeletal development, identifying regulatory function and novel mRNA targets.

The expression of miR-455-3p increases during chondrogenesis, and overexpression of miR-455-3p prior to differentiation results in a downregulation of chondrogenic marker genes. This suggests that although miR-455-3p is required during chondrogenesis, an upregulation of miR-455-3p results in a dysregulation of the differentiation process. Analysis of RNA-seq data from miR-455 null mouse articular cartilage and SW1353 cells inhibiting miR-455-3p supports this finding, demonstrating that differentially expressed genes in response to reduced miR-455 expression were associated with skeletal system development.

Overexpression of miR-455-3p in the developing chick limb bud also inhibits limb development. Microinjection of miR-455-3p into the limb bud of chick embryos resulted in a smaller limb bud size and delayed development phenotype. RNA-seq data revealed that differentially expressed genes were involved in mitochondrial dysfunction and a disruption to the cell cycle. The majority of these genes are not miR-455-3p predicted targets, however, they have a common promotor sequence for CREB1 suggesting regulation by the transcription factor. In the chick limb bud, CREB1 is downregulated by miR-455-3p and further analysis identified CREB1 as a direct target of miR-455-3p.

To conclude, this research indicates that miR-455-3p has a role in chondrogenesis, regulating the expression of CREB1, and possibly influencing chondrocyte proliferation. Within skeletal development, the impact of miR-455-3p demonstrates a significant regulatory mechanism to explore further.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 22 Aug 2022 10:12
Last Modified: 22 Aug 2022 10:12
URI: https://ueaeprints.uea.ac.uk/id/eprint/87538

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