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

From: Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk

ASD causal genes Region/neurons/cells in which gene function is affected Species Affected signaling pathway Phenotypes/downstream targets Citations
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+ Itpr3tf/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]
UBE3AT485A 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]