Autism spectrum disorder (ASD) is believed to result from abnormal development of neuronal networks and synaptic function (Sacai et al., 2020). It is estimated that worldwide one in 160 children has an ASD (62/10000). Based on epidemiological studies conducted over the past 50 years, the prevalence of ASD appears to be increasing globally (Elsabbagh et al., 2012). Syndromic forms unlike idiopathic forms include only 10% of cases often associated with malformations and/or dysmorphic properties. Syndromic forms originate from well-known genetic or genomic disorders that include neurofibromatosis, fragile X, tuberous sclerosis, Angelman and Rett syndromes (Benvenuto et al., 2009).
Stem cell factor (SCF) also named kit ligand, steel factor (SLF), is a cytokine that binds to the c-kit receptor (CD117). Its receptor, encoded by the proto-oncogene, c-kit, is a member of the class III family of intrinsic tyrosine kinase growth factor receptor. Both SCF and c-kit mRNAs are expressed in cells of the nervous system during development and in adulthood (Kim et al., 2003). c-Kit is expressed in neural stem cells and in their differentiated progeny (Erlandsson et al., 2004). During embryonic development, SCF mRNA is detectable in neural tube as early as at mouse embryonic day 9.5 (Keshet et al., 1991). In the adult nervous system, high level of SCF transcripts was found in the thalamus, cerebral cortex and cerebellum (Zhang and Fedoroff, 1997). Furthermore, c-kit has been shown to be expressed in neuroproliferative zones in the adult brain and in neuronal cultures (Jin et al., 2002).
The SCF or kit ligand is a cytokine mediating its biological effects by binding c-kit as its receptor. C-kit is a tyrosine 3 kinase receptor affecting downstream signaling pathways through its molecular functions, thereby inducing and enhancing the activity of these pathways (Lee et al. 2013). Moreover, activation of c-Kit signaling has been found to mediate cell survival, migration, and proliferation depending on the cell type. Signaling from c-kit is crucial for some aspects of the nervous system including neurogenesis and synapse formation (Lennartsson and Rönnstrand, 2012). Expression data also suggest that c-kit signaling may have important roles in the nervous system. Studies on mice carrying loss-of-function mutations in either c-kit or SCF have established a role for c-kit signaling in the spatial learning function of the hippocampal region of the brain (Katafuchi et al., 2000). Administration of SCF in animals leads to proliferation of primitive neurons. c-kit plays an important role in the migration of neuronal stem- and progenitor cells to sites of injury in the brain (Sun and Lee, 2004). It was shown that SCF induced functional improvement in chronic stroke is associated with a contribution to increasing neurogenesis through direct effects on stimulating neurons to form new neuronal networks. Systemic administration of SCF during the acute phase of experimental stroke reduces infarct size and ameliorates brain ischemia-induced neurological deficits (Zhao et al., 2007). Administration of anti-c-kit antibody into the cerebrospinal fluid leads to increased cell death in the developing cerebral cortex (Mashayekhi and Golizadeh, 2011). c-Kit knockout mice exhibit abnormalities in learning and memory (Katafuchi et al., 2000), suggesting potentially important roles for SCF/c-kit in normal brain physiology. In culture, recombinant SCF supports the survival of rat and chick neurons which express c-kit receptor (Hirata et al., 1993). Therefore, SCF/c-kit may act as a neurotrophic factor for c-kit expressing neurons.
A variety of integral membrane receptors, including c-Kit, can be released from the lipid bilayer by proteolysis to form soluble, truncated proteins. The soluble form of Kit (s-cKit) is produced by post-translational proteolytic cleavage of full length Kit (Kasamatsu et al., 2008). The proteases that generate soluble forms of membrane proteins are predominantly metalloproteinases or serine proteinases. The soluble receptors are smaller, consisting of the extracellular origin of the membrane-bound receptor and, in general, are able to bind to ligand with reduced affinity. The proteolytic cleavage of full-length Kit at the cell surface reduces the availability and density of full-length receptor and anchoring protein. s-Kit can bind both soluble and membrane-bound forms of the ligand (Merkwitz et al., 2011).
Mutations in genes involved in the regulation of the number, size, shape and strength of neuronal synapses and genes codifying for synaptic proteins were shown to be linked to ASD as well as to other neuropsychiatric and neurodevelopmental disorders (Sala et al., 2015; Verpelli and Sala, 2012). Due to potential important roles of SCF/c-Kit signaling in normal brain physiology including neurogenesis, synapse formation and spatial learning function of the hippocampal region of the brain, we aimed to study the serum concentrations of SCF and s-Kit in the risk prediction of ASD.