Growing a Cellular Tree With Healthy Branches

Univ. of Iowa biologists show how brain cells get the message to develop a signaling network.

When you think of a neuron, imagine a tree.

A healthy brain cell indeed looks like a tree with a full canopy. There’s a trunk, which is the cell’s nucleus; there’s a root system, embodied in a single axon; and there are the branches, called dendrites.

Neurons in your brain pass signals from one to another like they’re playing an elaborate, lightning-quick game of telephone, using axons as the transmitters and dendrites as the receivers. Those signals originate in the brain and are passed throughout the body, culminating in simple actions, such as wiggling a toe, to more complex instructions, such as following through on a thought.

Just as you can judge a healthy tree by its canopy, so too can scientists judge a healthy neuron by its dendritic branches. But it had been unclear what causes dendrites to grow, and where those instructions to grow come from.

Biologists at the University of Iowa have determined a group of genes associated with neurons help regulate dendrites’ growth. But there’s a catch: These genes, called gamma-protocadherins, must be an exact match for each neuron for the cells to correctly grow dendrites.

The findings may offer new insight into what causes aggressive or stunted dendrite growth in neurons, which could help explain the biological reasons for some mental-health diseases, as well as help researchers better understand brain development in babies born prematurely.

“Disrupted dendrite arborization is seen in the brains of people with autism and schizophrenia, so processes like the one we have uncovered here may have relevance to human disorders,” says Joshua Weiner, a molecular biologist at the UI and corresponding author on the paper, published online this month in the journal Cell Reports.

Gamma-protocadherins are called “adhesion molecules” because they stick out from a cell’s membrane to bind and hold cells together. The researchers learned about their role by giving a developing brain cell in a mouse the same gamma-protocadherin as in surrounding cells. When they did, the cells grew longer, more complex dendrites. But when the researchers outfitted a mouse neuron with a different gamma-protocadherin than the cells around it, dendritic growth was stunted.

The human brain is filled with neurons. Scientists think adults have 100 billion brain cells, each in close proximity to others and all seeking to make contact through their axons and dendrites. The denser a neuron’s dendritic network, the more apt a cell is to be in touch with another and aid in passing signals.

Gamma-protocadherins act like molecular Velcro, binding neurons together and instructing them to grow their dendrites. Weiner and his team figured out their role when they observed paltry dendritic growth in mouse brain cells where the gamma-protocadherins had been silenced.

The researchers went further in the new study. Using mice, they expressed the same type of gamma-protocadherin (labeled either as A1 or C3) in neurons in the cerebral cortex, a region of the brain that processes language and information. After five weeks, the neurons had sizeable dendritic networks, indicative of a healthy, normally functioning brain. Likewise, when they turned on a gamma-protocadherin gene in a neuron different from the gamma-protocadherin gene with the cells surrounding it, the mice had limited dendrite growth after the same time period.

That’s important because human neurons carry up to six gamma-protocadherins, meaning there are many combinations potentially in play. Yet, it seems the “grow your dendrite” signal only happens when neurons carrying the the same gamma-protocadherin gene pair up.

Image shows dendrites and neurons.
University of Iowa biologists have shown that neurons need exact gene matches to get the signal to grow dendrites, the branches in brain cells that help pass messages from the brain throughout the body. Left: An image of mouse neurons with developed, functioning dendrites (yellow and green), surrounded by other cells called astrocytes (in red). Lower right: A single neuron’s nucleus (yellow spot) with dendrites (yellow tendrils). Upper right: Arrows showing sites of contact between a neuron’s cell surface and an astrocyte. Middle right: the enlarged area of a neuron-dendritic network. Credit: Joshua Weiner lab/University of Iowa.

“The neurons actually care who they match with,” says Weiner, associate professor in the Department of Biology, part of the College of Liberal Arts and Sciences. “It takes what we knew from biochemical studies in a dish and shows that protocadherins really mediate these matching interactions in the developing brain.”

The team reports that star-looking cells called astrocytes also play a role in neurons’ dendrite development. Astrocytes are glial (Greek for “glue”) cells that help to bridge the gap between neurons and speed signals along. When the molecular binding between an astrocyte and neurons is an exact match, the neurons grow fully formed dendrites, the researchers report.

“Our data indicate that g-Pcdhs (gamma-protocadherins) act locally to promote dendrite arborization via homophilic matching and confirm that connectivity in vivo depends on molecular interactions between neurons and between neurons and astrocytes,” the authors write.

About this neurology research

Co-authors on the paper include Michael Molumby, a graduate student in the UI’s Interdisciplinary Graduate Program in Genetics, and Austin Keeler, who earned his doctorate in the UI’s Interdisciplinary Graduate Program in Neuroscience last December. The pair helped design the experiments, collected and analyzed data, and helped write the paper.

Funding: The National Institutes of Health and the March of Dimes Foundation, a non-profit organization devoted to improving babies’ health, funded the research.

Source: Richard Lewis – University of Iowa
Image Source: The image is credited to Joshua Weiner lab/University of Iowa.
Original Research: Full open access research for “Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity” by Michael J. Molumby, Austin B. Keeler, and Joshua A. Weiner in Cell Reports. Published online April 213 2016 doi:10.1016/j.celrep.2016.03.093


Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity

•Increasing γ-Pcdh homophilic matching promotes dendrite complexity in the cortex
•Inducing γ-Pcdh homophilic mismatching reduces dendrite complexity in the cortex
•Astrocytes regulate dendrite complexity cell non-autonomously via γ-Pcdh interactions
•γ-Pcdhs promote dendrite complexity through local interactions

Growth of a properly complex dendrite arbor is a key step in neuronal differentiation and a prerequisite for neural circuit formation. Diverse cell surface molecules, such as the clustered protocadherins (Pcdhs), have long been proposed to regulate circuit formation through specific cell-cell interactions. Here, using transgenic and conditional knockout mice to manipulate γ-Pcdh repertoire in the cerebral cortex, we show that the complexity of a neuron’s dendritic arbor is determined by homophilic interactions with other cells. Neurons expressing only one of the 22 γ-Pcdhs can exhibit either exuberant or minimal dendrite complexity, depending only on whether surrounding cells express the same isoform. Furthermore, loss of astrocytic γ-Pcdhs, or disruption of astrocyte-neuron homophilic matching, reduces dendrite complexity cell non-autonomously. Our data indicate that γ-Pcdhs act locally to promote dendrite arborization via homophilic matching, and they confirm that connectivity in vivo depends on molecular interactions between neurons and between neurons and astrocytes.

“Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity” by Michael J. Molumby, Austin B. Keeler, and Joshua A. Weiner in Cell Reports. Published online April 213 2016 doi:10.1016/j.celrep.2016.03.093

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