Table 1 Autism spectrum disorder (ASD) causal genes influencing WNT, BMP/TGF-β, SHH, FGF, and RA signaling pathways in vertebrates and invertebrates

5-HT GOF (gain-of-function)

Blood

Human

TGF-β

TGF-β pathway identified as a novel hyperserotonemia-related ASD genes

[18]

ALDH1A3

Human

RA

[135]

ANK3 LOF (loss-of-function)

P19 cells, proliferating neural progenitors of E16 mouse cortices, E15 brain slices

Mouse

WNT (canonical)

Increases proliferation of neural progenitor cells and nuclear β-catenin

[85]

APC LOF

Forebrain neurons, and hippocampal, cortical, and striatal regions

Mouse

WNT (canonical)

Learning and memory impairments and autistic-like behaviors (increased repetitive behaviors, reduced social interest)

[1]

BTBR T⁺ Itpr3^tf/J (BTBR) mice

Spleen and brain tissues

Mouse

TGF-β

Decreased TGF-β levels

[17]

CD38

Lymphoblastoid cell lines

Human and mouse

RA

Upregulation of CD38 by RA

[140, 141]

CHD8^−/− LOF

Whole

Mouse

WNT (canonical)

Embryonically lethal

[87]

CHD8^+/− LOF

Nucleus accumbens (NAc)

Mouse

WNT (canonical)

Macrocephaly, craniofacial abnormalities, and behavioral deficits; WNT signaling upregulates in the nucleus accumbens (NAc) region of the brain

[89]

CTNNB1 LOF

Parvalbumin interneurons

Mouse

WNT (canonical)

Impaired object recognition and social interactions; elevated repetitive behaviors; enhanced spatial memory

[66]

CTNNB1 cKO LOF

Dorsal neural folds

Mouse

WNT (canonical)

Spina bifida aperta, caudal axis bending, and tail truncation

[65]

CTNNB1 haploinsufficiency LOF

Whole

Human and mouse

WNT (canonical)

Neuronal loss, craniofacial anomalies, and hair follicle defects

[64]

DHCR7 LOF

MEFs

Mouse

SHH

Impaired SMO and reduced SHH signaling

[111]

DIXDC1 LOF

Mouse cortex

Human and mouse

WNT (canonical)

Impaired dendrite and spine growth, positive modulator of WNT signaling

[79]

Dlx5 GOF

2B1 cell line

Mouse

BMP

Upregulation of BMP binding endothelial regulator (Bmper)

[13]

DNlg4 LOF

NMJ

Drosophila

BMP

Reduced growth of neuromuscular junctions (NMJs) with fewer synaptic boutons

[10]

EN2 GOF

Post-mortem samples

Human

SHH

Elevated SHH expression

[117]

FGF22/FGF7 LOF

Hippocampal CA3 pyramidal neurons

Mouse

FGF

Impaired synapse formation

[124]

FMRP depletion

COS-7 cells

Monkey

BMP

Increase in BMPR2 and activation of LIMK1, stimulates reorganization of actin to promote neurite outgrowth and synapse formation

[11]

FOXN1

Human

RA

[135]

mGluR5 LOF

Cortical neurons

Mouse

FGF

Increased NGF and FGF10 mRNA levels

[125]

PGE2

Differentiating neuronal cells

Humans

WNT (canonical)

Upregulation of WNT3 and TCF4

[80, 93, 94]

PRICKLE2 LOF

Hippocampal neurons

Mouse

WNT (non-canonical)

Altered social interaction, learning abnormalities, and behavioral inflexibility

[40]

PTCHD1 LOF

Dentate gyrus

Mouse

SHH (hypothetical)

SHH independent; disrupted synaptic transmission

[109]

RERE

Human

RA

[137]

RORA LOF

Lymphoblastoid cell lines

Human

RA

Reduced protein levels of RORA and BCL-2 in autistic brain; aberrant methylation

[133]

TCF7L2 LOF

Human and mouse

WNT (canonical)

Required for thalamocortical axonal projection formation

[68,69,70,71]

UBE3A GOF

Prefrontal cortex

Mouse

RA

Negative regulation of ALDH1A2; impaired RA-mediated synaptic plasticity

[139]

ube3a LOF

NMJ

Drosophila

BMP

Compromised endocytosis in the NMJs and an upregulated BMP signaling in the nervous system

[12]

UBE3A^T485A LOF

HEK293T cells

Human

WNT (canonical)

Stabilizes nuclear β-catenin and stimulates canonical WNT signaling

[78]

WNT1, WNT2, WNT3, WNT9B

Human

WNT (canonical)

Elevated WNT3 expression in the prefrontal cortex of ASD patients

[34, 41,42,43,44,45]