Protocadherin 15 suppresses oligodendrocyte progenitor cell proliferation and promotes motility through distinct signalling pathways

Zhen, Yilan; Cullen, Carlie L.; Ricci, Raphael; Summers, Benjamin S.; Rehman, Sakina; Ahmed, Zubair M.; Foster, Antoinette Y.; Emery, Ben; Gasperini, Robert; Young, Karen

doi:10.1038/s42003-022-03470-1

Cited by 9 publications

(7 citation statements)

References 98 publications

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“…Somatic mutation of PCDH15 has been associated with metastasis in ocular adnexal sebaceous carcinoma [65]. PCDH15 knockdown significantly increases ERK phosphorylation and activation, increasing the proliferation of oligodendrocyte progenitor cells [66]. Our observation that PCDH15 mutations are associated with specific carcinoma ecotypes is an avenue for future investigation.…”

Section: Discussionmentioning

confidence: 69%

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis

Moreno,

Winham,

Alemozaffar

et al. 2023

Cancers

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Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.

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Section: Discussionmentioning

confidence: 69%

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis

Moreno,

Winham,

Alemozaffar

et al. 2023

Cancers

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“…5d ). These genes included several candidates of interest, such as Protocadherin 15 ( Pcdh15 ), associated with oligodendrocyte progenitors and the in vitro suppression of their proliferation 85 , which we found suffered an age-dependent increase in gene expression coupled to a reduction of H3K27me3 levels which was reversed with EE in old individuals (Fig. 5e ), along with the Receptor Tyrosine Kinase Like Orphan Receptor 1 gene ( Ror1 ), which is a synapse-formation- and neural progenitor regulator 86 , 87 found decreased in cellular models of Alzheimer’s 88 , for which we observed the EE-associated recuperation of its expression and opposing H3K27me3 levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Pérez,

Tezanos,

Peñarroya

et al. 2024

Nat Commun

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Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline.

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“…This analysis reveals that mIPCs are enriched for both neuronal and radial glial markers, including RBFOX1, ADGRV1 , and NRG1 , as well as for cell cycle genes. In contrast, gIPCs are enriched for glial markers, including OLIG1/2 and SLC1A2 , and markers associated with migration, including ERBB4 and PCDH15 15 , 39 (Fig. 2c , Supplementary Data 7 ).…”

Section: Resultsmentioning

confidence: 99%

An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics

et al. 2022

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Late prenatal development of the human neocortex encompasses a critical period of gliogenesis and cortical expansion. However, systematic single-cell analyses to resolve cellular diversity and gliogenic lineages of the third trimester are lacking. Here, we present a comprehensive single-nucleus RNA sequencing atlas of over 200,000 nuclei derived from the proliferative germinal matrix and laminating cortical plate of 15 prenatal, non-pathological postmortem samples from 17 to 41 gestational weeks, and 3 adult controls. This dataset captures prenatal gliogenesis with high temporal resolution and is provided as a resource for further interrogation. Our computational analysis resolves greater complexity of glial progenitors, including transient glial intermediate progenitor cell (gIPC) and nascent astrocyte populations in the third trimester of human gestation. We use lineage trajectory and RNA velocity inference to further characterize specific gIPC subpopulations preceding both oligodendrocyte (gIPC-O) and astrocyte (gIPC-A) lineage differentiation. We infer unique transcriptional drivers and biological pathways associated with each developmental state, validate gIPC-A and gIPC-O presence within the human germinal matrix and cortical plate in situ, and demonstrate gIPC states being recapitulated across adult and pediatric glioblastoma tumors.

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Protocadherin 15 suppresses oligodendrocyte progenitor cell proliferation and promotes motility through distinct signalling pathways

Cited by 9 publications

References 98 publications

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis

A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics

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