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

Abstract

Background: The development of an autistic brain is a highly complex process as evident from the involvement of various genetic and non-genetic factors in the etiology of the autism spectrum disorder (ASD). Despite being a multifactorial neurodevelopmental disorder, autistic patients display a few key characteristics, such as the impaired social interactions and elevated repetitive behaviors, suggesting the perturbation of specific neuronal circuits resulted from abnormal signaling pathways during brain development in ASD. A comprehensive review for autistic signaling mechanisms and interactions may provide a better understanding of ASD etiology and treatment.

Main body: Recent studies on genetic models and ASD patients with several different mutated genes revealed the dysregulation of several key signaling pathways, such as WNT, BMP, SHH, and retinoic acid (RA) signaling. Although no direct evidence of dysfunctional FGF or TGF-β signaling in ASD has been reported so far, a few examples of indirect evidence can be found. This review article summarizes how various genetic and non-genetic factors which have been reported contributing to ASD interact with WNT, BMP/TGF-β, SHH, FGF, and RA signaling pathways. The autism-associated gene ubiquitin-protein ligase E3A (UBE3A) has been reported to influence WNT, BMP, and RA signaling pathways, suggesting crosstalk between various signaling pathways during autistic brain development. Finally, the article comments on what further studies could be performed to gain deeper insights into the understanding of perturbed signaling pathways in the etiology of ASD.

Conclusion: The understanding of mechanisms behind various signaling pathways in the etiology of ASD may help to facilitate the identification of potential therapeutic targets and design of new treatment methods.

Keywords: Autism spectrum disorder; BMP/TGF-β; FGF; Neurodevelopmental disorders; Retinoic acid (RA); SHH; Signaling crosstalk; WNT.

Fig. 1

Possible interactions between ASD causal genes and WNT signaling. Most molecules (red) encoded by the ASD-associated genes are either core components of WNT signaling pathways, such as WNTs, APC, β-catenin, TCF7L2, and PRICKLE2, or their modulators, such as DIXDC1, PGE2, UBE3A, and CHD8. ANK3 interacts with β-catenin at the plasma membrane. Note: plus sign indicates upregulation; minus sign indicates downregulation

Fig. 2

Possible interactions between ASD causal genes and SHH signaling. The genes encoded for PTCHD1, EN2, and DHCR7 are potential ASD genes. Note: minus sign indicates downregulation; question mark indicates undefined role of PTCHD1 in SHH signaling

Fig. 3

Possible interactions between ASD causal genes and RA signaling. UBE3A affects ALDH1A expression and thereby affects retinoic acid signaling pathway. RORA is associated with ASD which influences NLGN1. The RA signaling coregulator RERE is also associated with ASD

Fig. 4

ASD causal genes affecting BMP signaling and potential crosstalk with other signaling pathways. ASD causal genes-encoded proteins, such as NLGN3/4, FMR1, DLX, and UBE3A, interact with BMP signaling pathway which may further affect WNT signaling. It should be noted that overexpression of UBE3A affects WNT and RA signaling pathways. However, its loss-of-function affects BMP signaling. Note: plus sign indicates upregulation; minus sign indicates downregulation