Table 1 Examples of hcASD genes that converge on and disrupt RAS/ERK, PI3K/AKT, WNT and β-catenin signaling pathways

FMR1 ^b,c,d

PI3K/AKT

Fmr1 knock-out mice have elevated activation of PI3K/AKT signaling pathway, affecting synaptic plasticity with behavioral and cognitive defects. Downregulation of PI3K in prefrontal cortex of Fmr1 null mice ameliorates aberrations in protein synthesis, dendritic spine density and cortical network activity.

FOXG1 ^b

PI3K/AKT

The PI3K/AKT signaling pathway affects cell fate determination and neural migration by regulating FOXG1.

NLGN3 ^a,c,d

PI3K/AKT

NLGN3 secretion by active neurons enhances proliferation of glial cells by activation of PI3K/AKT pathway. Also affects synaptic development.

PTEN ^a,b,c,d

PI3K/AKT

Pten^+/- mice show high activity in PI3K/AKT and β-catenin signaling resulting in enhanced proliferation of radial glial cells and cortical overgrowth; neuronal hypertrophy, hypertrophic and ectopic dendrites and axonal tracts; increased synapses; and hyperconnectivity of prefrontal cortex with amygdala. Pten also involves in neural migration.

RELN ^b,c,d

PI3K/AKT

PI3K/AKT signaling pathway affects cell fate determination and neural migration by regulating RELN. While RELN promotes neuronal maturation, synaptic formation and plasticity, it appears to be more important for dendrite and spine development via PI3K/AKT/mTOR pathway.

SHANK3 ^a,c,d

PI3K/AKT

Mice with Shank3 mutations show deficits in synaptic function, hippocampal LTP and motor performance that can be improved with IGF1 treatment. Also affects neurogenesis.

MECP2 ^a,b,c,d

PI3K/AKT and RAS/ERK

iPS-derived RG cells from Rett syndrome patients with MECP2 mutation exhibit excess proliferation through activation of PI3K/AKT and downregulation of RAS/ERK pathways. Neurons with MECP2 knock-down fail to attain a unipolar/bipolar shape, display abnormal migration and reduced cortical thickness. Neuron models of MECP2 mutations lead to abnormalities in soma size, dendritic arborizations, spine density, and neuronal firing that may be partially rescued by inhibiting Pten gene or IGF1 treatment.

ARID1B ^a,c,d

PI3K/AKT, WNTand β-catenin

ARID1B suppression delays cell cycle re-entry. Mice with Arid1b knock-down show suppressed IGF1, a mediator of PI3K/AKT and β-catenin pathways, resulting in decreased dendritic arborization and accumulation of aberrant dendritic spines and altered synaptic transmission.

16p11.2^a,d

RAS/ERK

16p11.2 is one of most recurrent CNVs in ASD and encompasses multiple genes including ERK1. Its deletion dysregulates RAS/ERK with effect on proliferation and neurogenesis of murine neural progenitor cells. 16p11.2 mutation mouse models show reduced RAS/ERK activity, reduced protein synthesis and cognitive impairments.

ERBIN ^a,d

RAS/ERK

ERBIN has an inhibitory effect on RAS/ERK signaling pathway. Upregulation or downregulation of Erbin leads to enhanced or decreased differentiation of PC12 neurons, respectively.

KAT2B ^a,b,c,d

RAS/ERK

Null mutations lead to dysregulation of RAS/ERK and disruption of the pyramidal cell layer organization.

NF1 ^d

RAS/ERK

Mice with Nf1 null mutations show dysregulated RAS/ERK pathway and deficits in spine morphology, glutamate and GABA release, hippocampal LTP and learning abilities.

SYNGAP1 ^c,d

RAS/ERK

SYNGAP1 acts as RAS inhibitor, and heterozygote mutations in mice show premature neurons, elevated excitatory synaptic transmission, reduced axonal branching and synaptic boutons in inhibitory neurons, and deficits in behavior and cognition. Rescuing Syngap1 in adulthood did not benefit the mice, underscoring its role in prenatal and early post-natal brain development.

CHD8 ^a,d

WNT and β-catenin

CHD8 knock-down disrupts G1/S phase, dysregulates proliferation in neural progenitor and stem cells and causes brain overgrowth. Chd8 mutations in mice result in abnormalities in striatal circuitry and synaptic physiology

CTNND2 ^a,c,d

WNT and β-catenin

Affects proliferation of glioma cells and involved in glioblastoma. Regulates spine morphology; mutations decrease spines and excitatory synapses in hippocampal neurons in rodents. Ctnnd2 mutation in mouse models have impaired spatial learning and fear conditioning.