Non-canonical Wnt Signaling through Ryk Regulates the Generation of Somatostatin- and Parvalbumin-Expressing Cortical Interneurons

Abstract

GABAergic interneurons have many important functions in cortical circuitry, a reflection of their cell diversity. The developmental origins of this diversity are poorly understood. Here, we identify rostralcaudal regionality in Wnt exposure within the interneuron progenitor zone delineating the specification of the two main interneuron subclasses. Caudally situated medial ganglionic eminence (MGE) progenitors receive high levels of Wnt signaling and give rise to somatostatin (SST)-expressing cortical interneurons. By contrast, parvalbumin (PV)-expressing basket cells originate mostly from the rostral MGE, where Wnt signaling is attenuated. Interestingly, rather than canonical signaling through b-catenin, signaling via the non-canonical Wnt receptor Ryk regulates interneuron cell-fate specification in vivo and in vitro. Indeed, gain of function of Ryk intracellular domain signaling regulates SST and PV fate in a dose-dependent manner, suggesting that Ryk signaling acts in a graded fashion. These data reveal an important role for non-canonical Wnt-Ryk signaling in establishing the correct ratios of cortical interneuron subtypes.

Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis

“…Autism spectrum disorder has been linked with thousands of genes which are themselves organized into networks which affect brain development including synapse formation and function, neurite growth and neuronal proliferation and migration ( Gazestani et al, 2019 ) and many of which are perturbed by cannabinoids. Key amongst these pathways is the critical Wnt -β-catenin system signaling ( Gazestani et al, 2019 ) which is a key body and brain morphogen and is powerfully perturbed by cannabinoids ( Xian et al, 2018 ; McKenzie et al, 2019 ; Nalli et al, 2019 ; Reece and Hulse, 2019a, 2019c, 2019d, 2020b, 2020c ).…”

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

“…Recent evidence demonstrates that initial interneuron subtype fate is specified within the GEs (Alvarez-Dolado et al, 2006; Fishell and Kepecs, 2020; Larimer et al, 2016; Larimer et al, 2017; Nery et al, 2002; Taniguchi et al, 2013; Wichterle et al, 1999; Wichterle et al, 2001) and that initial aspects of interneuron subtype identity are established as interneuron progenitors exit the cell cycle (Mayer et al, 2018; Mi et al, 2018). Several factors contribute to these initial fate decisions, including spatial gradients of secreted cues and transcription factors (Brandao and Romcy-Pereira, 2015; Flames et al, 2007; McKenzie et al, 2019; Tyson et al, 2015; Wonders et al, 2008; Xu et al, 2010), temporal birthdates during embryogenesis (Bandler et al, 2017; Inan et al, 2012; Miyoshi and Fishell, 2011; Rymar and Sadikot, 2007), and the mode of neurogenesis (Petros et al, 2015). However, given the incredible diversity of interneuron subtypes, we still lack a comprehensive understanding of the mechanisms that regulate early stages of interneuron fate determination during embryogenesis.…”

Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+ cortical interneurons

“…Of note, the CGE gives rise to other classes of CINs, including the vasoactive intestinal peptide (VIP) expressing and the REELIN+/SST-groups (Miyoshi et al, 2010). While recent studies have examined the role of transcription factors that influence MGE and CGE CIN development (Hu et al, 2017a;Mayer et al, 2018;Pai et al, 2019), few reports have assessed how cellular signaling proteins regulate these processes (Malik et al, 2019;McKenzie et al, 2019). After their initial programming in the MGE, CINs tangentially migrate into and laminate the neocortex.…”