MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor

Abstract

In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions.

Introduction

Autism spectrum disorders (ASD), which include autistic disorder, Asperger's syndrome, and pervasive developmental disorder (PDD)-not otherwise specified, are a group of neurodevelopmental syndromes that share a disease onset during early brain development and maturation (Abrahams and Geschwind, 2008, Geschwind and Levitt, 2007, Walsh et al., 2008). There have been no unifying neuropathologic or neurobiological features that define ASDs. The diagnosis is based on clinical assessment of some core behavioral features, including impaired communicative skills, atypical social behavior, and restricted interests and repetitive behaviors. Two cardinal features of ASD are heritability and heterogeneity. Heritability refers to the fact that autism has evidently the strongest genetic components of all the developmental neuropsychiatric disorders. This is exemplified by the 82–92% concordance rate for autism among monozygotic twins as compared with ~ 10% concordance rate for dizygotic twins (Abrahams and Geschwind, 2008, Bailey et al., 1995, Constantino et al., 2013). Heterogeneity is reflected by the enormous number (> 200) of gene loci (Aldinger et al., 2011, Ebert and Greenberg, 2013, Piggot et al., 2009) that contribute to the risk of developing ASD, hence imposing a major challenge for the identification of causative genes. While this genetic heterogeneity can manifest as noncoding variations, de novo mutations that produce syndromic disorders with autistic traits, copy number variations, and chromosome abnormalities (Marshall et al., 2008, Nakatani et al., 2009, Piggot et al., 2009, Sebat et al., 2007, Walsh et al., 2008), their functional implication spans even wider, from neuronal growth, projection and motility, GTPase/Ras-mediated signaling and cytoskeletal organization, proteolysis, to activity-dependent synaptic remodeling (Levitt and Campbell, 2009, Pinto et al., 2010). Thus, to gain insights into the underlying mechanisms of ASD will require a multidisciplinary approach focusing on brain regions, neural networks, and cellular substrates.

ASD is a complex disorder and, as such, identification of causative genes has been hampered by many inherent problems, such as multiple gene effects/interactions, environmental factors, gene–environment interactions, variable penetrance for each individual gene, and genetic heterogeneity. Many well-established autism risk genes encode proteins that are involved in the molecular networks controlling formation and function of the glutamatergic synapse, the submicron-scale structure that connects individual neurons into functional networks capable of computational outputs. These well-established genes include, but are not limited to, NRXN1, PTEN, SHANK3, UBE3a, NF1, NLGN3/4, CNTNAP2, SYNGAP1, and FMR1 (Alarcon et al., 2008, Bourgeron, 2009, Clement et al., 2012, Durand et al., 2007, Penagarikano et al., 2011, Piggot et al., 2009, Tabuchi et al., 2007, Yashiro et al., 2009). These molecules function by mediating pre- and postsynaptic assembly, scaffolding the synaptic structure, controlling neurotransmitter release, and affecting the activity-dependent structural changes, processes critical to sculpting our experience into neuronal circuits to guide future behavior. Not surprisingly, pathogenic mutations of the previously mentioned ASD genes during development have been shown to lead to synaptic dysfunction, impact the brain circuit, and disrupt the balanced excitatory/inhibitory brain networks (Ebert and Greenberg, 2013, Rubenstein and Merzenich, 2003, Tabuchi et al., 2007).

It is important to note, however, that synaptogenesis and neural circuit dynamics are relatively late events during the neurodevelopmental timeline. Prior to these events, the production and positioning of neurons in a correct cellular and network context must take place in order for synaptogenesis and circuit remodeling to occur. These early histogenic events are determined by genetic programs encoding neurogenesis, migration, neurite outgrowth and polarization, and axon guidance at critical developmental stages. At the cellular level, once a neuron is born, it migrates a long distance before arriving at its destination and differentiating. Neurons extend two classes of processes: a single axon to carry its output and several dendrites to collect information input. Once this neuronal polarity is established, the axon navigates through a complex environment to find its target, and dendrites undergo extensive growth and branching. The last step in forming functional circuitry is the establishment of synaptic connections between different neurons (Bradke and Dotti, 2000, Craig and Banker, 1994, Mueller, 1999, Tessier-Lavigne and Goodman, 1996). Two major types of synapses, excitatory and inhibitory, coexist within any functional circuitry, and their balanced action on the postsynaptic neurons shapes their functional output (Rubenstein & Merzenich, 2003). Therefore, aberrant genetic programs during this early extended timeline (as compared to impaired synaptic function at later stages) may profoundly affect brain function as well. Consistently, autism risk genes have been shown to control wide aspects of developmental events including neurogenesis, synaptogenesis, glutamatergic transmission, endosomal trafficking, and protein turnover (Ebert and Greenberg, 2013, Qiu et al., 2012, Walsh et al., 2008). As diverse as these risk genes appear, they may converge on a final common molecular pathway to disrupt developmental outcomes that perturb circuit formation and maturation.

The development of the central nervous system (CNS) is a complex process driven by a myriad of factors including a large family of growth factors and their receptors. Protein receptor tyrosine kinases (RTKs), which are cell-surface receptors for many polypeptide growth factors, hormones, and cytokines (Robinson, Wu, & Lin, 2000), regulate many aspects of neuronal physiology, including neurogenesis and survival, differentiation and migration, patterned connectivity, and plasticity. The human gene MET, which encodes MET RTK (Cooper et al., 1984), has emerged as a prominent risk factor for ASD (Campbell et al., 2006, Campbell et al., 2009, Jackson et al., 2009, Sousa et al., 2009, Thanseem et al., 2010). MET plays a pleiotropic role in cell proliferation, motogenesis, differentiation, and survival in many tissue types (Birchmeier et al., 2003, Maina et al., 1998). The ligand for MET receptor, hepatocyte growth factor (HGF), is a polypeptide growth factor that activates MET (Naldini, Weidner, et al., 1991). Both MET and HGF are expressed in the developing brain, with distinct spatial and temporal profiles (Judson, Amaral and Levitt, 2011, Judson et al., 2009, Jung et al., 1994). Genetic studies from multiple laboratories have found that functional MET promoter variants are associated with differential risks for ASD. Consistently, clinical imaging and animal studies have provided evidence that disrupted MET signaling levels produce both morphological and functional alterations in neurons in those brain regions implicated in producing the ASD endophenotypes. In this chapter, we will briefly discuss how MET signaling might be ideally situated to regulate circuits and modify neuronal function. We review recent literature and hypothesize that MET signaling plays a critical role in balancing neuronal growth, functional maturation, and establishing functional circuits.