Sex-and Region-Dependent Expression of the Autism-Linked ADNP Correlates with Social- and Speech-Related Genes in the Canary Brain

Abstract

The activity-dependent neuroprotective protein (ADNP) syndrome is an autistic-like disorder, instigated by mutations in ADNP. This syndrome is characterized by developmental delays, impairments in speech, motor function, abnormal hearing, and intellectual disabilities. In the Adnp-haploinsufficient mouse model, many of these impediments are evident, appearing in a sex-dependent manner. In zebra finch songbird (ZF; Taeniopygia guttata), an animal model used for song/language studies, ADNP mRNA most robust expression is observed in the cerebrum of young males, potentially corroborating with male ZF exclusive singing behavior and developed cerebral song system. Herein, we report a similar sex-dependent ADNP expression profile, with the highest expression in the cerebrum (qRT-PCR) in the brain of another songbird, the domesticated canary (Serinus canaria domestica). Additional analyses for the mRNA transcripts of the ADNP regulator, vasoactive intestinal peptide (VIP), sister gene ADNP2, and speech-related Forkhead box protein P2 (FoxP2) revealed multiple sex and brain region-dependent positive correlations between the genes (including ADNP). Parallel transcript expression patterns for FoxP2 and VIP were observed alongside specific FoxP2 increase in males compared with females as well as VIP/ADNP2 correlations. In spatial view, a sexually independent extensive form of expression was found for ADNP in the canary cerebrum (RNA in situ hybridization). The songbird cerebral mesopallium area stood out as a potentially high-expressing ADNP tissue, further strengthening the association of ADNP with sense integration and auditory memory formation, previously implicated in mouse and human.

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms

“…Our previously published studies have suggested that ADNP/NAP regulate FOXP2 in the tongue [ 51 ] and that NAP regulates FOXP2 in the brain [ 69 ]. Furthermore, we showed that the expression of ADNP is highly correlated with FOXP2 expression in the brain [ 70 ].…”

Understanding autism spectrum disorders with animal models: applications, insights, and perspectives

“…Although no animal model can fully capture the behavior and genetic complexity of ASD, as an experimental language learning animal model, songbirds can supplement the shortcomings of rodent genetic models and provide essential insights into communication deficiencies. For instance, zebra finches communicate through learned vocalizations and can be used to simulate language communication disorders ( Ahmadiantehrani & London, 2017 ; Hacohen-Kleiman et al, 2020 ; Panaitof, 2012 ). Moreover, recent genomic research has identified potential genetic substrates for the evolution and regulation of vocal communication ( Warren et al, 2010 ).…”

Avian models for brain mechanisms underlying altered social behavior in autism

“…The sex- and age-related expression of ADNP mRNA was reported in different areas (cerebellum, cerebrum, brainstem) of the zebra finch ( Hacohen-Kleiman et al, 2015 ), with a distinct sexual dimorphism (young males expressing higher levels of ADNP than females, in agreement with the notion that only males perform courtship singing). The gene expression profile was largely confirmed in the domesticated canary, and ADNP mRNA was found to be enriched mainly in the mesopallium, harboring centers for sensory integration and higher auditory processing ( Hacohen-Kleiman et al, 2020 ).…”