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Developmental biology - Brain Formation

MTSS1 protein controls neuron branching

How one protein helps manage the complex branching of neurons in our brain...

A protein called "MetastasisMetastasis-suppressor 1" (MTSS1) activates one signalling pathway while inhibiting another - playing a dual role in determining how neurons form and branch in our brains. The research is published in the journal Cell Reports.

Researchers at the Institute for Integrated Cell-Material Sciences (iCeMS) along with colleagues in Japan investigated how MTSS1 affects large neuron branches developing in the cortex of our cerebellum neurons called Purkinje cells.
Purkinje neurons are among the largest cells in the human brain, occupying the outer layer of the cerebellum located at the base of the skull. Each is composed of a large "trunk-like" cell from which intricate tree-shaped branches extend.

Location of cerebellum
Location of cerebellum in the brain. Illustration: Stanford University

These branches grow to completely fill all available space in order to receive information from every signal in the immediate area. These branches also retract when comming into contact with other Purkinje branches. This allows neurons to cover the maximum area possible, while minimizing duplication in signal reception.

Previous studies show that MTSS1 may be involved in Purkinje branch development, but few supporting details exist.

Professor Mineko Kengaku is a developmental neurobiologist working on the dynamic movements of developing neurons. By reconstructing brain cell architecture in petri dishes, Kengaku and her team believe they can help in developing new treatments for damaged brains.
Kengaku's team found by inhibiting the function of MTSS1 in Purkinje cells, baby mice had incomplete branching at the tops of Purkinje cells. This indicates MTSS1 is important in regulating the development of branching - a conclusion supported in computer simulations.

Upon further investigation, Kengaku's team found how MTSS1 regulates Actin A the protein forming the skeletal base for neuron branching by using two competing pathways.

Findings in Purkinje Cell Research:

MTSS1 activates a pathway called ARP2/3
ARP2/3 stimulates Actin filaments to grow at 70 angle to 'mother filament'
Inhibiting MTSS1 stimulates growth of Dendrites

MTSS1 also binds to and inhibits the protein DAAM1
DAAM1 forms straight unbranched Actin filaments (competing with ARP2/3?)
Dendrites in contact with neighboring Dendrites, retract.

This is the first time MTSS1 was identified as a DAAM1 inhibitor in vertebrate neurons.

MTSS1 loss decreases dendritic arbor complexity in cerebellar Purkinje cells
MTSS1 loss increases branch retraction by contact of longer dendritic protrusions
Dendritic protrusion shape is governed by competition between ARP2/3 and formins
MTSS1 directly inhibits actin nucleation by the formin DAAM1 in dendritic protrusions

Dendritic filopodia of developing neurons function as environmental sensors, regulating the spatial organization of dendrites and proper targeting to presynaptic partners. Dendritic filopodia morphology is determined by the balance of F-actin assembled via two major nucleating pathways, the ARP2/3 complex and formins. The inverse-BAR protein MTSS1 is highly expressed in Purkinje cells (PCs) and has been shown to upregulate ARP2/3 activity. PCs in MTSS1 conditional knockout mice showed dendrite hypoplasia due to excessive contact-induced retraction during development. This phenotype was concomitant with elongated dendritic filopodia and was phenocopied by overactivation of the actin nucleator formin DAAM1 localized in the tips of PC dendritic protrusions. Cell biology assays including single-molecule speckle microscopy demonstrated that MTSS1s C terminus binds to DAAM1 and paused DAAM1-mediated F-actin polymerization. Thus, MTSS1 plays a dual role as a formin inhibitor and ARP2/3 activator in dendritic filopodia, determining final neuronal morphology..

Authors: Kelly Kawabata Galbraith, Kazuto Fujishima, Hiroaki Mizuno, Sung-Jin Lee, Takeshi Uemura, Kenji Sakimura, Masayoshi Mishina, Naoki Watanabe, Mineko Kengaku.

About Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS)
At iCeMS, our mission is to explore the secrets of life by creating compounds to control cells, and further down the road to create life-inspired super materials that confront the myriad problems that afflict modern society. In only a decade, collaborative research at iCeMS has resulted in significant cutting-edge scientific discoveries, and the creation of over 1500 unique materials. We will keep turning our inspirations into purposeful, transformative innovations for the practical benefit of society.

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Inhibiting MTSS1 in Purkinje cells of baby mice leads to the incomplete growth of neuron 'branches'
at the ends of Purkinje cells. WILD TYPE refers to "normal." Image credit: Kyoto University iCeMS.

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