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1.
PLoS Biol ; 21(8): e3002212, 2023 08.
Article in English | MEDLINE | ID: mdl-37540708

ABSTRACT

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 ß1-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.


Subject(s)
Adaptor Proteins, Signal Transducing , Dystroglycans , Integrin beta1 , Neuroglia , Animals , Mice , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cell Movement/physiology , Cerebral Cortex/metabolism , Dystroglycans/genetics , Dystroglycans/metabolism , Integrin beta1/genetics , Integrin beta1/metabolism , Neuroglia/metabolism , Neurons/physiology , Signal Transduction/physiology
2.
J Cell Sci ; 134(20)2021 10 15.
Article in English | MEDLINE | ID: mdl-34515305

ABSTRACT

The advent of modern single-cell biology has revealed the striking molecular diversity of cell populations once thought to be more homogeneous. This newly appreciated complexity has made intersectional genetic approaches essential to understanding and probing cellular heterogeneity at the functional level. Here, we build on previous knowledge to develop a simple adeno-associated virus (AAV)-based approach to define specific subpopulations of cells by Boolean exclusion logic (AND NOT). This expression by Boolean exclusion (ExBoX) system encodes for a gene of interest that is turned on by a particular recombinase (Cre or FlpO) and turned off by another. ExBoX allows for the specific transcription of a gene of interest in cells expressing only the activating recombinase, but not in cells expressing both. We show the ability of the ExBoX system to tightly regulate expression of fluorescent reporters in vitro and in vivo, and further demonstrate the adaptability of the system by achieving expression of a variety of virally delivered coding sequences in the mouse brain. This simple strategy will expand the molecular toolkit available for cell- and time-specific gene expression in a variety of systems.


Subject(s)
Neurons , Recombinases , Animals , Gene Expression , Mice , Recombinases/genetics
3.
Sci Rep ; 8(1): 680, 2018 01 12.
Article in English | MEDLINE | ID: mdl-29330522

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 ß-chimaerin is expressed by a small population of late-born, premigratory granule cells. ß-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 ß-chimaerin as an intracellular mediator of Cerebellar Granule Cell radial migration.


Subject(s)
Cerebellum/metabolism , Neoplasm Proteins/metabolism , Animals , Cell Movement , Cell Proliferation , Cerebellum/chemistry , Cerebellum/cytology , Genotype , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Neurons/metabolism
4.
Nature ; 536(7616): 338-43, 2016 08 18.
Article in English | MEDLINE | ID: mdl-27509850

ABSTRACT

Williams syndrome 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 Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.


Subject(s)
Brain/pathology , Williams Syndrome/pathology , Adolescent , Adult , Apoptosis , Calcium/metabolism , Cell Differentiation , Cell Shape , Cellular Reprogramming , Cerebral Cortex/pathology , Chromosomes, Human, Pair 7/genetics , Dendrites/pathology , Female , Frizzled Receptors/deficiency , Frizzled Receptors/genetics , Haploinsufficiency/genetics , Humans , Induced Pluripotent Stem Cells/pathology , Male , Models, Neurological , Neural Stem Cells/pathology , Neurons/pathology , Phenotype , Reproducibility of Results , Synapses/pathology , Williams Syndrome/genetics , Young Adult
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