The autism-mutated ADNP plays a key role in stress response

Abstract

Activity-dependent neuroprotective protein (ADNP), discovered and first characterized in our laboratory (IG), is vital for mammalian brain formation and presents one of the leading genes mutated de novo causing an autistic syndrome, namely the ADNP syndrome. Furthermore, a unique mouse model of Adnp-haploinsufficiency was developed in the laboratory (IG), with mice exhibiting cognitive and social deficiencies. ADNP is regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP). In this respect, PACAP was independently identified as a sexual divergent master regulator of the stress response. Here, we sought to determine the impact of the Adnp genotype and the efficacy of PACAP pre-treatment when subjecting Adnp+/− mice to stressful conditions. Significant sex differences were observed with Adnp+/− males being more susceptible to stress in the object and social recognition tests, and the females more susceptible in the open field and elevated plus maze tests. Splenic Adnp expression and plasma cortisol levels in mice were correlated with cognition (male mice) and anxiety-related behavior. These findings were further translated to humans, with observed correlations between ADNP expression and stress/cortisol content in a young men cohort. Altogether, our current results may establish ADNP as a marker of stress response.

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

“…Additionally, the ADNP regulating peptide PACAP [ 12 ] was also shown to regulate muscle function in protection against outcome measures in a model of spinobulbar muscular atrophy [ 83 ]. Our most recent results also indicated Adnp regulation of the Adcyap1r1 transcript, encoding the PACAP-specific, PAC1 receptor with a significant increase in bladder Adcyap1r1 seen in Adnp +/− versus Adnp +/+ females and correction of the female Adnp +/− levels to the Adnp +/+ levels by NAP treatment [ 10 ].…”

“…These findings suggest a cross-regulation of ADNP and PACAP functions, with the PAC1 receptor antagonist, PACAP(6–38), reducing urinary bladder frequency and pelvic sensitivity in mice exposed to repeated variate stress [ 48 ] and with the majority of ADNP syndrome patients suffering from bladder training delay [ 5 ]. Furthermore, PACAP ameliorates Adnp +/− -deficiencies that are exacerbated by stress [ 12 ].…”

“…A significant sexual dichotomy was revealed, coupled to muscle and age-specific gene regulation. Thus, Adnp regulated myosin light chain ( Myl ) transcript in the gastrocnemius muscle, the language acquisition gene forkhead box protein P2 ( Foxp2 ) transcript in the tongue muscle, and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor PAC1 mRNA (Adcyap1r1) in the bladder, with PACAP, linked to bladder function [ 11 ] and partly controlling Adnp expression [ 12 ]. A sex-dependent Adnp -regulated gene transcript correlation to gait patterns (CatWalk) was discovered, placing ADNP as a muscle-regulating gene/protein [ 10 ].…”

Animal models of autism: a perspective from autophagy mechanisms

“…ADNP is a gene encoding a transcription factor located on the long arm of chromosome 20 (20q13.13). ADNP syndrome is characterized by global developmental delays, ID, speech barriers, and motor dysfunctions [51] . Deletions in this chromosomal region cause ID [52] .…”

“…ADNP controls the expression of genes during embryonic and postnatal development, including neurogenesis-crucial genes and BECN1 [53] . Given the direct relationship between ADNP and MAP1-LC3B, as well as the connection of autism with eukaryotic initiation factor 4E (Eif4e) and its tight relationship with autophagy, ADNP is also inevitable to play a role in autism and autophagy [51,54] . ADNP knock-out mice resulted in embryonic death during the closure of the neural tube [53] .…”