PTEN in Autism and Neurodevelopmental Disorders

Abstract

Phosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes phosphatidylinositol 3-phosphate kinase (PI3K)/AKT signaling. Although there is a strong association of PTEN germline mutations with cancer syndromes, they have also been described in a subset of patients with autism spectrum disorders with macrocephaly characterized by impairments in social interactions and communication, repetitive behavior and, occasionally, epilepsy. To investigate PTEN's role during neurodevelopment and its implication for autism, several conditional Pten knockout mouse models have been generated. These models are valuable tools to understand PTEN's spatiotemporal roles during neurodevelopment. In this review, we will highlight the anatomical and phenotypic results from animal studies and link them to cellular and molecular findings.

Figure 1.

Phosphatase and tensin homolog (PTEN) structure and canonical phosphatidylinositol 3-phosphate kinase (PI3K)/PTEN signaling cascade. (A) Schematic representation of PTEN protein domains, together with the localization of germline missense mutations associated with ASD, developmental delay, and mental retardation (for a review, see Spinelli et al. 2015). Additional missense mutations not shown in the scheme: M1I, K6I/E. (B) Canonical PI3K/PTEN signaling cascade. Activating phosphorylation is depicted in green, and inhibitory phosphorylation is depicted in red. Dashed lines denote multiple steps.

Figure 2.

Stages of murine neurodevelopment. Boxes indicate peaks in the processes, dashed lines indicate that the process is active to a distinct extent. (Figures created from data in Reemst et al. 2016 and Thion and Garel 2017.)

Figure 3.

Cross talk between phosphatidylinositol 3-phosphate kinase (PI3K)/AKT/phosphatase and tensin homolog (PTEN) cascade with other signaling axes during proliferation and differentiation. (A) Cross talk with Wnt/β-catenin signaling. (B) Cross talk with Notch signaling. (C) Cross talk with insulin-like growth factor (IGF) signaling.

Figure 4.

Cortical development in phosphatase and tensin homolog (PTEN)-positive and -negative brains. NSC, Neuronal stem cell; NPC, neuronal precursor cell; RG, radial glia; MZ, marginal zone; CP, cortical plate; IZ, intermediate zone; SVS, subventricular zone; VZ, ventricular zone.

Figure 5.

Processes in postmitotic neurons that are altered in the gene encoding phosphatase and tensin homolog (PTEN) loss. (A) Regulation of growth cone collapse. (B) Regulation of spine density, morphology, and excitability. (C) Regulation of synaptic plasticity. (D) Regulation of axonal myelination. sEPSC, Spontaneous excitatory postsynaptic current; PI3K, phosphatidylinositol 3-phosphate kinase; NMDA, N-methyl-d-aspartate; LTP, long-term potentiation; LTD, long-term depression.