Cas Family of Adaptor Proteins are Required in Radial Glial Cells for Cortical Lamination

Laminar organization of the cortex requires neurons to exit the cell cycle, locomote, and assemble into six distinct layers. Neurons encounter multiple permissive and repulsive guidance cues simultaneously during cell migration. The molecular mechanism of how these cues are interpreted by migrating cells is not well understood. To gain insight into the mechanisms of signal transduction that participate during cortical migration and lamination, we studied the three embryonically-expressed Cas signaling adaptor proteins (p130Cas, CasL, and Sin) to uncover the signaling events essential cortical development. We hypothesize that the Cas family of proteins mediate adhesion signal transduction during corticogenesis as they are known to mediate integrin-dependent signals at focal adhesion complexes. Here, we provide in vivo genetic evidence that Cas proteins serve a functional and redundant role during cortical lamination. Cas triple conditional knock-out (CasTcKO) mice display severe cortical phenotypes that resemble cobblestone lissencephaly. The malformation in CasTcKO brains include ectopic clusters of neurons in the marginal zone and meninges. Furthermore, all excitatory neuronal subpopulations are disrupted in CasTcKO mutants. Defects in neuronal positioning appear to be non-neuronal autonomous, suggesting that Cas genes are required in radial glial cells for proper cortical lamination. Disruption to radial glial interactions with the basement membrane resulted in disarrayed radial glial basal processes and ectopic proliferating cells. Molecular epistasis analysis placed Dystroglycan, a known regulator of glial-pial interactions, upstream of Cas phosphorylation. Furthermore, this dystroglycan-dependent recruitment of phosphorylated Cas to radial glial endfeet requires β1 integrin signaling. Overall, our data support an essential role for Cas adaptor proteins during cortical lamination by acting downstream of dystroglycan and β1 integrin in radial glial cells

In Conversation : Blueprints for the Otherwise

In this Frank Davis Memorial Lecture JJ Chan and Sunshine Wong will work through some ideas surrounding ‘critical care’ as an ethos for arts organisational infrastructure. Just over a year ago, JJ demanded ‘a radical reconfiguration of the artistic and curatorial conscience’, a call that was echoed in many variations as 2020 unfolded into global pandemic and unrest. Beyond institutional declarations of solidarity and Instagram black squares, what does this work actually involve? How does an organisational body ‘reconfigure’ itself? This conversation will describe the desires, aims and emergent processes of the 12-month residency programme Blueprints for the Otherwise at Bloc Projects, Sheffield. It will situate the speakers’ respective and collective positions in relation to the social and cultural events of the past year to pave the way for ‘critical care’ as an organisational ethos: ‘critical’ in the sense of urgency; ‘critical’ in the meaningful ways we nurture those around us. About the series ‘Asian Art after Quarantine’: Since the outbreak of the Covid-19 pandemic in early 2020, there has been a surge in racist attacks against Asian and Asian diasporic people across the globe; from everyday microaggressions to the recent mass shootings in Atlanta, USA, in March 2021. Yet, international media coverage has continued to disproportionally focus on the ‘China threat’ instead of giving voice and visibility to Asian communities. In solidarity with social justice movements and organisations such as #iamnotavirus, Stop AAPI Hate and StopDiscriminAsian (SDA), the 2021 Frank Davis Lecture Series presents a series of dialogues and conversations centred on Chinese and British-Chinese diasporic artistic experience in a turbulent year marked by city-wide quarantines and isolation, a scarcity of funding and public platforms for the arts, the unmasking of institutional structures of racism and anti-Asian violence. The Frank Davis Memorial Lecture Series is one of two annual distinguished lecture series at The Courtauld. This series was established in 1989, as a result of a bequest from the F.M. Kirby Foundation, in honour of Frank Davis, who was a critic for Country Life magazine. The bequest has allowed The Courtauld to invite internationally renowned scholars to come to the institute to speak about their work in a public forum

The RacGAP β-Chimaerin is essential for cerebellar granule cell migration

Abstract During mammalian cerebellar development, postnatal granule cell progenitors proliferate in the outer part of the External Granule Layer (EGL). Postmitotic granule progenitors migrate tangentially in the inner EGL before switching to migrate radially inward, past the Purkinje cell layer, to achieve their final position in the mature Granule Cell Layer (GCL). Here, we show that the RacGAP β-chimaerin is expressed by a small population of late-born, premigratory granule cells. β-chimaerin deficiency causes a subset of granule cells to become arrested in the EGL, where they differentiate and form ectopic neuronal clusters. These clusters of granule cells are able to recruit aberrantly projecting mossy fibers. Collectively, these data suggest a role for β-chimaerin as an intracellular mediator of Cerebellar Granule Cell radial migration

An adhesion signaling axis involving Dystroglycan, β1-Integrin, and Cas adaptor proteins regulates the establishment of the cortical glial scaffold.

The mature mammalian cortex is composed of 6 architecturally and functionally distinct layers. Two key steps in the assembly of this layered structure are the initial establishment of the glial scaffold and the subsequent migration of postmitotic neurons to their final position. These processes involve the precise and timely regulation of adhesion and detachment of neural cells from their substrates. Although much is known about the roles of adhesive substrates during neuronal migration and the formation of the glial scaffold, less is understood about how these signals are interpreted and integrated within these neural cells. Here, we provide in vivo evidence that Cas proteins, a family of cytoplasmic adaptors, serve a functional and redundant role during cortical lamination. Cas triple conditional knock-out (Cas TcKO) mice display severe cortical phenotypes that feature cobblestone malformations. Molecular epistasis and genetic experiments suggest that Cas proteins act downstream of transmembrane Dystroglycan and β1-Integrin in a radial glial cell-autonomous manner. Overall, these data establish a new and essential role for Cas adaptor proteins during the formation of cortical circuits and reveal a signaling axis controlling cortical scaffold formation

A human neurodevelopmental model for Williams syndrome

Williams syndrome (WS) is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with WS lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23(1–5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioral pathologies in humans, remains largely unexplored. Here, we investigate neural progenitor cells (NPCs) and cortical neurons derived from WS and typically developing (TD) induced pluripotent stem cells (iPSCs). WS NPCs have an increased doubling time and apoptosis compared to TD NPCs. Using an atypical WS subject(6, 7), we narrowed this cellular phenotype to a single gene candidate, FZD9. At the neuronal stage, WS-derived layers V/VI cortical neurons were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in WS neurons were validated after Golgi staining of postmortem layers V/VI cortical neurons. This human iPSC model(8) fills in the current knowledge gap in WS cellular biology and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain

The Role of Frugivorous Bats in Tropical Forest Succession

Discussion of successional change has traditionally focused on plants. The role of animals in producing and responding to successional change has received far less attention. Dispersal of plant propagules by animals is a fundamental part of successional change in the tropics. Here we review the role played by frugivorous bats in successional change in tropical forests. We explore the similarities and differences of this ecological service provided by New and Old World seed‐dispersing bats and conclude with a discussion of their current economic and conservation implications. Our review suggests that frugivorous New World phyllostomid bats play a more important role in early plant succession than their Old World pteropodid counterparts. We propose that phyllostomid bats have shared a long evolutionary history with small‐seeded early successional shrubs and treelets while pteropodid bats are principally dispersers of the seeds of later successional canopy fruits. When species of figs (Ficus ) are involved in the early stages of primary succession (e.g. in the river meander system in Amazonia and on Krakatau, Indonesia), both groups of bats are important contributors of propagules. Because they disperse and sometimes pollinate canopy trees, pteropodid bats have a considerable impact on the economic value of Old World tropical forests; phyllostomid bats appear to make a more modest direct contribution to the economic value of New World tropical forests. Nonetheless, because they critically influence forest regeneration, phyllostomid bats make an important indirect contribution to the economic value of these forests. Overall, fruit‐eating bats play important roles in forest regeneration throughout the tropics, making their conservation highly desirable