Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder

Abstract

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like "novel drugs for ASD" and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.

Keywords: Asperger’s syndrome; autism spectrum disorder; hedgehog signaling pathway; neuropathological alterations.

Figure 1

Wnt signaling pathway: Binding of Wnt to frizzled receptors (FZD) and LRP5/6; phosphorylation of LRP5/6 by GSK-3β; CK1α attracts the Dvl to the membrane and then inhibits the destruction complex; β-catenin in the cytoplasm is translocated to the nucleus, dislodging Groucho repressor and recruiting various BCL9 co-factors by binding to LEF/TCF. BCL9 and CBP/p300 permit the transcription of Wnt targeted genes, which are involved in cell differentiation, proliferation, and adhesion.

Figure 2

The hedgehog (hh) signaling pathway showing hh ligands (Shh, Dhh, Ihh) and their receptor Ptch 1. Upon binding with Ptch1, the pathway causes internalization, and Smo inhibition is released. After this, Smo is phosphorylated causing a cascade activation through downstream regulation, and Gli1/2 is processed into the activator forms GliA and GliB. After translocation of GliA into the nucleus, it stimulates target gene expression. The transcriptional repressor precursor Gli3 remains inactive.

Figure 3

Retinoic acid (RA) signaling pathway. Retinoic acid is synthesized intracellularly from retinol, which first is converted into retinaldehyde by the enzyme alcohol dehydrogenase or retinol dehydrogenase. The reversible conversion of retinal to retinol is mediated by the enzyme retinal reductase (DHRS3). Retinal is irreversibly oxidized to become retinoic acid (RA) by the enzyme retinaldehyde dehydrogenase (ALDHs). Retinoic acid inside the cell binds to receptors present on the surface of the nucleus (RAR, ROR, and RXR) and recognizes consistent response elements (RARE, RORE, and RXRE) along with the DNA, which activates the expression of different target genes.