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Fred Hutchinson Cancer Center developmental biologist Cecilia Moens, PhD recently received a prestigious Javits Neuroscience Investigator Award. The new grant will allow Moens to better understand the cues that help growing neurons find their way through a developing embryo to form sensory-motor neural circuits. Her work will reveal how intimate contacts between cells, and the arrangement of key molecules along these cells, help guide a neuron even when its goal — the brain — is far away.
“This is a brand-new project that absolutely could not have occurred without Javits funding,” Moens said.
The Javits Award, given by the National Institute of Neurological Disorders and Stroke, is named after the late Senator Jacob K. Javits, who had amyotrophic lateral sclerosis, or ALS, and championed research into disorders of the brain and nervous system. The award provides seven years of support to investigators who have exhibited superior competence and outstanding productivity. NINDS staff and the National Advisory Neurological Disorders and Stroke Council nominate particularly noteworthy applications for other NINDS funding. The innovative and paradigm-challenging nature of Moens’ proposal helped garner her the Javits Award.
Overturning old ideas about pathfinding axons
Using zebrafish embryos, Moens studies the 3D construction of neural circuits during development. Zebrafish embryos are transparent and develop outside their mothers’ bodies, so Moens can watch zebrafish development under a microscope without harming the fish fry or impeding their natural maturation.
As an embryo develops, its neurons send out their long, tendril-like axons to connect to other neurons and also muscles and areas like the skin that receive sensory input.
“This is very important for your nervous system development,” Moens said. “It has to happen for us to be able to form the neural circuits that allow us to take sensory information from our environment, transmit it to the brain, do some computation, and then respond appropriately.”
No single neuron reaches all the way from the skin to the brain, or from the brain to the muscles. Instead, several nerve cells link up to create a relay. Neurons that connect nerve cell to nerve cell are called interneurons. In her new award, Moens will focus on the cues that guide a specific type of interneuron as it makes a critical directional decision.
Moens is studying commissural interneurons in the spinal cord (from the Latin for seam or join), which connect sensory neurons on one side of the body with brain areas on the other, as part of the neural circuit that governs rhythmic movements like walking. To send sensory information from far-flung body regions to the brain, commissural interneuron axons must cross the midline of the spinal cord before turning to extend towards the brain.
“All of those steps have been studied in some detail, especially those early steps of crossing the midline — really, really well studied. Many of the molecules involved in determining an interneural axon’s path have been described in textbooks. But that's not to say that they're well understood,” Moens said. "Those molecules were discovered a long time ago, but even in very recent years, our understanding of how those molecules work has changed. The way that they function is still subject to investigation and is resulting in paradigm-changing, textbook-changing discoveries.”
Moens expects her Javits-funded work to rewrite our understanding of the way that certain molecules orchestrate the critical choice a commissural neuron axon makes after crossing the midline: to turn toward the brain and complete the circuit, or turn toward the tail — and fail.
Currently, it’s thought that, like truffle-hunting pigs, the commissural interneuron axons follow their noses, homing in on molecules released by the brain that grow in concentration as the axon nears the brain. Textbooks and research papers are full of examples of so-called “long-range guidance cues” that axons were thought to respond to — but more and more recent studies suggest that these molecules actually act at very short ranges, Moens said.
Instead of forming a stable gradient (which is difficult to do in an ever-changing embryo), “those molecules are functioning moment-to-moment through cell contacts. … As the axon is moving through the tissue, it’s detecting differences very locally between one cell and the next — or even two sides of the same cell — so it’s contacting and responding, and contacting and responding, again and then again, without some long-range view,” she said. “It’s sort of, act locally, think globally: The ultimate goal is to get to the brain, but the brain is not the thing you’re responding to.”
Exploring the guiding cues
In this project, Moens is also exploring a new idea about how growing commissural interneurons use close contacts with other cells as a guide to the far-away brain. In their search for the brain, these axons grow through the neural tube, the structure that will become the spinal cord and brain. Her Javitz Award will enable Moens to test the idea that the cells lining the neural tube, along which the commissural interneuron axons feel their way, are set up in a directional manner that draws the axon in the right direction. She will also determine how the developing embryo establishes that directionality.
Directionality in biology is also called polarity. Sometimes polarity occurs across a cell, as when cells lining the intestine have different structures and functions on the side facing out to the intestinal space than the side facing into the body. But Moens is studying how polarity that occurs along cells aids the nerve cells’ pathfinding.
For example, there are cilia, tiny hair-like structures projecting from cells, that line Fallopian tubes and beat in one direction, ferrying mature eggs along the cells lining these tubes until they reach the uterus. There are other examples: the hairs that grow in one direction along our limbs, or the cilia that move cerebrospinal fluid in one direction through the spinal column.
“All of those have a directionality to the behavior of the cell, the function of the cell and the structure of the cell,” Moens said.
Her work focuses on a specific set of molecules, which make up the planar cell polarity pathway, or PCP pathway, that create this kind of polarity in many tissues around the body. Moens believes that the PCP pathway is critical for getting commissural interneuron axons all the way to the brain.
“What we're hypothesizing in this grant is that the neural epithelium — which is the neural tube — is polarized, thanks to the planar cell polarity pathway, and that that polarization is functionalized for axon guidance,” she said. “And that’s a new idea.”
Molecules in the PCP pathway stud the outer layer of the cells that the axon probes as it decides where to travel. Moens believes that these molecules help the probing axon detect polarity differences between and along cells in the neural tube, which it uses in its quest for the brain.
“It’s been a pet project of mine,” she said. “I’m particularly chuffed to get this award because it is based on experiments I have been doing as a team with my technician Jason Stonick. We’re really excited to now have the stable funding to push this fascinating project forward.”
