Mecp2 regulatestnfaduring zebrafish embryonic development and acute inflammation

Abstract

Mutations in MECP2 cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of MECP2 also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MECP2 in controlling immune and inflammatory responses. Here, we used mecp2-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2 deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis. By contrast, expression of the proinflammatory cytokine tumor necrosis factor alpha (Tnfa) was consistently downregulated in mecp2-null animals during development, representing the earliest developmental phenotype described for MECP2 deficiency to date. Expression of tnfa was unresponsive to inflammatory stimulation, and was partially restored by re-expression of functional mecp2. Thus, Mecp2 is required for tnfa expression during zebrafish development and inflammation. Finally, RNA sequencing of mecp2-null embryos revealed dysregulated processes predictive for Rett syndrome phenotypes.

Rett syndrome: a neurological disorder with metabolic components

“…isolated the first null mecp2 Q63*/Q63* zebrafish model, which does not recapitulate features of the human disorder [ 110 , 111 ]. Instead, the fish are viable and reproduce normally, but display minor motor abnormalities and a shortened lifespan, possibly due to immune deficiencies [ 112 ]. In 2017, Chen et al .…”

Intestinal Candida parapsilosis isolates from Rett syndrome subjects bear potential virulent traits and capacity to persist within the host

“…Furthermore, there is a critical interplay between inflammation and oxidative stress in the underlying mechanisms [ 57 ]. More recently, MeCP2 has been reported to act as an epigenetic regulator of immune and inflammatory responses during zebrafish development [ 58 ]. In this context, the bacterial and fungal microbiota dysbiosis demonstrated in our previous metataxonomics study from the same cohort of subjects [ 26 ] and the presence of putative virulent, pro-inflammatory intestinal C. parapsilosis strains could represent an additional factor in RTT’s gastrointestinal pathophysiology and subclinical inflammation.…”

Prenatal Neuropathologies in Autism Spectrum Disorder and Intellectual Disability: The Gestation of a Comprehensive Zebrafish Model

“…Additionally, researchers have shown that inflammatory molecules influence fetal gene expression, including dysregulation of ASD-ID genes associated with mTOR and EIF4E dependent signaling [30]. A recent ASD-ID zebrafish model looked at larval immunological function to determine whether immune responses were affected in a Methyl-CpG-Binding Protein 2 ( MECP2 ) null background [46]. MECP2 mutations cause Rett Syndrome, which includes symptoms associated with inflammation, such as gastrointestinal disturbances and oxidative stress [47].…”

“…MECP2 mutations cause Rett Syndrome, which includes symptoms associated with inflammation, such as gastrointestinal disturbances and oxidative stress [47]. Mecp2 mutants exhibited decreased expression of tumor necrosis factor a ( tnfa) during early embryogenesis and increased expression of interleukin-1b and interleukin-10 throughout larval stages [46]. Inflammatory molecules from these genes are needed to stimulate the bodies response to a disturbance and promote tissue repair [46].…”

“…Mecp2 mutants exhibited decreased expression of tumor necrosis factor a ( tnfa) during early embryogenesis and increased expression of interleukin-1b and interleukin-10 throughout larval stages [46]. Inflammatory molecules from these genes are needed to stimulate the bodies response to a disturbance and promote tissue repair [46]. Therefore, these changes in gene expression may be a response to tissue disturbances or oxidative stress, including a dysregulated inflammatory response of the gastrointestinal tract.…”