Научная статья на тему 'Shaping the dendritic tree: the role of arhgap33 in neocortical development and disease'

Shaping the dendritic tree: the role of arhgap33 in neocortical development and disease Текст научной статьи по специальности «Биологические науки»

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Opera Medica et Physiologica
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Текст научной работы на тему «Shaping the dendritic tree: the role of arhgap33 in neocortical development and disease»


Memory loss in Alzheimer's disease (AD) results from "synaptic failure". Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and AD. To understand the basis for memory loss in AD we performed a series of mechanistic studies of hippocampal synaptic spines in mouse models of familial AD (FAD). In our experiments we used presenilin 1 (PS1) M146V knockin (PS1KI) and APPKI models of FAD.

In the course of these studies we discovered an existence of spine maintenance pathway that is mediated by neuronal store-operated Ca2+ entry (nSOC) in postsynaptic spines (Sun et al, 2014). We established that nSOC pathway plays a key role in stability of mushroom spines by constitutively activating synaptic CaMKII kinase. We further demonstrated that synaptic nSOC is controlled by stromal interaction molecule 2 (STIM2) and that STIM2-nSOC-CaMKII pathway is compromised in PS1KI and APPKI neurons, in aging neurons and in sporadic AD brains due to downregulation of STIM2 protein (Sun et al., 2014; Zhang at al 2015). Moreover, we have demonstrated that expression of STIM2 protein rescues synaptic nSOC and mushroom spine loss in PS1KI and APPKI hippocampal neurons (Sun et al., 2014; Zhang at al 2015) and protects mushroom spines from amyloid synaptotoxicity (Popugaeva at al, 2015). These studies suggested that STIM2-nSOC pathway is a potentially important AD therapeutic target, and that activators and positive modulators of this pathway may have a utility for treatment of synaptic loss and memory decline in aging and AD.


1. Suya Sun, Hua Zhang, Jie Liu, Elena Popugaeva, Nan-Jie Xu, Stefan Feske, Charles L. White, III, and Ilya Bezproz-vanny (2014) Reduced Synaptic STIM2 Expression and Impaired Store-Operated Calcium Entry Cause Destabilization of Mature Spines in Mutant Presenilin Mice. Neuron, vol 82, pp 79-93.

2. Elena Popugaeva, Ekaterina Pchitskaya, Anastasiya Speshilova, Sergey Alexandrov, Hua Zhang, Olga Vlasova, Ilya Bezprozvanny (2015) STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. Molecular Neurodegeneration, 10:37.

3. Hua Zhang, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Takashi Saito, Takaomi Saido and Ilya Bezprozvanny (2015) Neuronal store-operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse model of Alzheimer's disease. J. Neuroscience, vol 35, pp 13275-13286.

Shaping the Dendritic Tree: the Role of Arhgap33 in Neocortical Development and Disease

Steffen Schuster1, Marion Rivalan2, Ulf Strauss3, Victor Tarabykin4, Marta Rosârio1*

1 Dendritic Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin, Berlin, Germany;

2 Humboldt University Berlin, Institute of Cognitive Neurobiology, Charité Universitätsmedizin Berlin;

3 Ionic Current Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin;

4 Cortical Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin,Berlin. * Presenting e-mail: marta.rosario@charite.de

Neuropsychiatrie developmental disorders, such as autism spectrum disorders (ASD) and schizophrenia, are typically characterized by alterations in social behavior. At a cellular level, these conditions have been linked to aberrant development and maturation of the dendritic tree. We show here that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP/ARHGAP33 regulates autism-like social behavior in the mouse as well as the formation of the dendritic tree and its maturation into a synaptically-connected branched structure (1, 2). ARHGAP33-deficient mice show cortical thinning associated with poorly branched dendritic trees. We demonstrate that inhibition of the small GTP-binding protein Cdc42 in postmitotic neurons is necessary for activation of the actin-binding protein cofilin and hence for proper branching of the neuronal dendritic tree during development of the mammalian neocortex. Furthermore, we demonstrate that these early steps are dependent on ARHGAP33, which acts as the main GTPase-activating protein for Cdc42 during neocortical development.

ARHGAP33 also has critical functions in the maturation of dendritic spines and in synapse formation in the neocortex. Surprisingly, we show that these later developmental functions are independent of its Cdc42 GAP activity.

However we show that ARHGAP33 also directly interacts with several members of the MAGUK family of scaffold proteins and that, in mature neurons, it concentrates at the postsynaptic site. Furthermore we show that ARHGAP33 regulates the phosphorylation and subcellular localization of the MAGUK family protein and major postsynaptic component, PSD-95 as well as surface expression of the AMPA receptor, thereby providing a molecular basis for autism-like social behavior in the absence of ARHGAP33.





1. Rosario M, Schuster S, Juttner R, Parthasarathy S, Tarabykin V, Birchmeier W. Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin. Genes Dev 2012 Aug 1; 26(15): 1743-1757.

2. Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, Parthasarathy S, Lajko D, Rosenmund C, Shoichet SA, Winter Y, Tarabykin V, Rosario M. NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse. Mol Psychiatry 2015 Sep; 20(9): 1120-1131.

The Suppressors of Cytokine Signalling Socs6 and Socs7 are Essential for Cortical Layering and Reelin Signalling

Anne K. Voss* and Tim Thomas

Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia.

* Presenting e-mail: avoss@wehi.edu.au

Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the reelin signalling pathway have been identified, the molecular and ultimate cellular consequences of reelin signalling remain unknown. Specifically, it is unclear if termination of reelin signalling is as important for normal cortical neuron migration as activation of reelin signalling.


The aim of this project was to determine the role of members of the suppressors of cytokine signalling (SOCS) family of negative regulators of cell signalling in reelin signalling and cortical layer formation.


The methods used included mice that were single or double deficient for Socs6 and/or Socs7, histological analysis, immunofluorescence, BrdU birth dating, telencephalon explant and cortical neuron migration cultures, protein affinity purification, immunoprecipitation, immunoblotting or mass-spectrometry, isothermal titration calorimetry and functional mutation.


We discovered that combined loss of the suppressors of cytokine signalling, SOCS6 and SOCS7, recapitulated the cortical layer inversion seen in mice lacking reelin and led to a dramatic increase in the reelin signalling molecule disabled (DAB1) in the cortex. The SRC homology domains of SOCS6 and SOCS7 bound DAB1 ex vivo. Mutation DAB1Y300F greatly diminished binding and protected from degradation by SOCS6. Phosphorylated DAB1 was elevated in cortical neurons in the absence of SOCS6 and SOCS7.


We concluded that constitutive activation of reelin signalling was equally detrimental as lack of activation. We hypothesise that by terminating reelin signalling, SOCS6 and SOCS7 may allow new cycles of reelin signalling to occur and that these may be essential for cortical neuron migration.

A Dynamic Unfolded Protein Response Controls Cortical Neurogenesis

Laurent Nguyen*

GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, Belgium.

* Presenting e-mail: lnguyen@ulg.ac.be

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