Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

Abstract

De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERα-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERα axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers.

PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy

“…pathway ( Figure 1E). In the top 15 enriched pathways both estrogen and oxytocin signalling pathways were also identified, which have been previously been implicated in PCDH19-GCE (39). Further analysis of the 302 DE genes identified clusters of genes with bonafide roles in cell-cell adhesion and/or cadherin signalling, neuronal differentiation and maturation, and negative regulators of cellular proliferation.…”

Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study

“…In recent years, much effort has been focused on molecular genetic studies of PCDH19‐related epilepsy, with the purpose of elucidating the pathogenic bases of this syndrome . Multiple hypotheses have been considered for the pathogenesis, particularly the mechanisms of cellular interference and allopregnanolone deficiency due to neurosteroid‐metabolizing enzyme downregulation .…”

Cellular and behavioral characterization ofPcdh19mutant mice: subtle molecular changes, increased exploratory behavior and an impact of social environment

“…Although recent studies have shed light into the different functions of PCDH19 (Pederick et al 2016;Hayashi et al 2017;Pham et al 2017;Bassani et al 2018;Homan et al 2018;Pederick et al 2018, reviewed in Gerosa et al 2019Gécz and Thomas 2020), just exactly how mutations in this cell adhesion protein lead to the distinct symptoms associated with EIEE9 is still not well understood. Here we present a detailed analysis of neuronal sub-types expressing Pcdh19/PCDH19 in the cortex of mice and humans.…”

“…PCDH19 is involved in different processes, ranging from neurulation and organization of the optic tectum in zebrafish (Emond et al 2009;Cooper et al 2015) to neurogenesis and regulation of GABAergic transmission in mammals (Fujitani et al 2017;Bassani et al 2018;Homan et al 2018;Lv et al 2019). In addition, PCDH19 is involved in gene expression regulation with estrogen receptor alpha (Pham et al 2017) and mutations in PCDH19 lead to a deficiency of the neurosteroid allopregnanolone and of other neuroactive steroids (Tan et al 2015;Trivisano et al 2017).…”