Differential Regulation of Microtubule Severing by APC Underlies Distinct Patterns of Projection Neuron and Interneuron Migration

Abstract

Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. Two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial vs. tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex.

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

“…At least some APC proteins also regulate actin dynamics, working together with Diaphanous (Breitsprecher et al, 2012; Jaiswal et al, 2013), to control focal adhesion turnover (Juanes et al, 2017). When considering cytoskeletal effects of APC loss, however, it is critical to rule out places where Wnt signaling itself regulates downstream cytoskeletal events (e.g., Elbaz et al, 2016;Eom et al, 2014;Hayden et al, 2007;Nakagawa et al, 2017;Yokota et al, 2009). Other destruction complex or signalosome proteins also have cytoskeletal roles.…”

KTN80 confers precision to microtubule severing by specific targeting of katanin complexes in plant cells

“…On the other hand, prior work has shown that katanin regulates neuron development in vivo. For instance, defective MT severing is associated with neuronal abnormalities, including Alzheimer's disease where abnormal aggregation of the MT-associated tau protein might interfere with its role in preventing excess MT severing (Qiang et al, 2006;Eom et al, 2014;Mao et al, 2014). Additionally, katanin is essential for both male and female fertility via modulating the assembly of meiotic spindles (McNally et al, 2006;Loughlin et al, 2011;O'Donnell et al, 2012;Smith et al, 2012).…”

TIPsy tour guides: how microtubule plus-end tracking proteins (+TIPs) facilitate axon guidance

“…Like other plus-end stabilizing proteins, APC was found to be greatly enriched in the nervous system during axon growth and navigation (Bhat et al, 1994 ; Koester et al, 2007 ). A series of works emerged that pointed to GSK3-modulated APC in multiple roles within the early nervous system, including neuronal polarity, migration, and axon specification, providing some added assurance that this interaction was an important regulator of MT dynamics in neural development (Dobashi et al, 2000 ; Shi et al, 2004 ; Koester et al, 2007 ; Purro et al, 2008 ; Eom et al, 2014 ; Mohn et al, 2014 ; Onouchi et al, 2014 ). APC preferential localization was shown to accumulate on the “turning” side of the growth cone as it encountered a substrate border, predicting turning behavior (Koester et al, 2007 ; Figure 2 ).…”