Dab1 expression level controls Reelin-induced PI3K-Akt activation in early GABAergic neurons

Abstract

Disabled-1 (Dab1) is a key regulator of the Reelin signaling cascades and controls many neurodevelopmental processes, including pyramidal neuron migration, dendrite growth, and spine formation. Dab1 is phosphorylated upon the binding of Reelin to Very low density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2) receptors, resulting in activation of a series of downstream signaling pathways, including Phosphoinositide 3-kinase (PI3K)/Akt, Lissencephaly 1 (Lis1), Crks/C3G, and Extracellular signal-regulated kinase 1/2 (Erk1/2). Dab1 is then rapidly degraded via the proteasome pathway. In humans, REELIN and DAB1 are genetically associated with several psychiatric disorders, such as schizophrenia and autism spectrum disorder. Although a subset of GABAergic neurons express Reelin and are continuously exposed to Reelin from early developmental stages through adulthood, most studies have only investigated the role of Reelin in the development and function of pyramidal neurons; as such the role of Reelin in GABAergic neurons remains poorly understood. In this study, we isolated primary neurons from mouse medial ganglionic eminence (MGE) at embryonic day 14.5 that 98-99 % were composed of GABAergic neurons. Using MGE-isolated GABAergic neurons, we studied the quantitative differences in Reelin signaling and expression of related genes in these neurons for the first time. Reelin supplementation did not activate PI3K-Akt signaling in most GABAergic neurons, but it did activate the signaling pathway in Somatostatin-positive GABAergic neurons. Dab1 was transcriptionally repressed in early GABAergic neurons, demonstrating the selective activation of Reelin signaling between subsets of neurons. This study provides quantitative evidence and contributes insights into the molecular mechanisms underlying the limited effects of Reelin on Dab1-related developmental activities in the majority of GABAergic neurons during brain development.

Keywords: Dab1; GABAergic neurons; Medial ganglionic eminence; Phosphoinositide 3-kinase; Reelin.