(Above: In double cortex syndrome, causing epilepsy and mental retardation, an extra cortex forms just beneath the cerebral cortex [right]. The causative DCX mutation interferes with migration of neurons during the cortex’s early development. Courtesy Walsh Lab)
The journal Neuron, celebrating its 25th anniversary, recently picked one influential neuroscience paper from each year of the publication. In this two-part series, we feature the two Boston Children’s Hospital’s scientists who made the cut. The Q&A below is adapted with kind permission from Cell Press. (See part 1)
Key to well-tuned brain function is the migration of neurons to precise locations as the brain develops. The long journey begins deep inside the brain and ends in the outer cerebral cortex—where our highest cognitive functions lie. Christopher Walsh, MD, PhD, has shown that several genetic mutations causing neurodevelopmental disorders disrupt this neuronal migration, landing neurons in the wrong places. Each gene governs a specific sub-task: one kicks off the migration process; others stop migration when neurons have arrived in the right location.
Walsh and colleagues found their first migration-related gene in children with double-cortex syndrome—in which an extra cortex forms just beneath the cerebral cortex, causing epilepsy and mental retardation. They identified mutations in a gene they named doublecortin (DCX). “When we first cloned DCX, in 1998, we had no idea how it might work,” Walsh recalls.
In 1999, in two back-to-back papers, Walsh’s team and separate team led by Jamel Chelly, PhD, showed that DCX modulates neuronal migration by regulating the organization and stability of rigid tube-like structures inside cells, known as microtubules, that form part of the cytoskeleton. This interior skeleton gives cells shape and enables them to interact with their environment.
Aside from setting the stage for a better understanding of how the cortex develops, these studies were among the first to establish that cytoskeletal defects can contribute to cognitive or other neurologic problems in children.
What stimulated your interest in neuroscience?
I took a course in psychology as a college freshman with Alan Leshner, PhD (later director of the National Institute on Drug Abuse and publisher of Science) who discussed brain structure and classic experiments in psychology. He was a really entertaining lecturer and got me hooked.
What influences have shaped your research?
Outstanding mentors. My thesis advisor, Ray Guillery, PhD, got me interested in the amazing wonder of brain development, how proper connections define our mind, and how genetics allows us to dissect them. During my neurology residency at Massachusetts General Hospital, Verne Caviness, MD, introduced me to studying cerebral cortical development using mutations, and Joseph Martin, MD, PhD, inspired me to study the human genetics of neurological disease.
In terms of your scientific career, what are you most proud of?
When our lab started studying brain malformations, I thought we were only doing it to study mechanisms of development. But at the same time there was a brewing controversy about the genetic causes of developmental brain diseases of children, like intellectual disability, epilepsy and autism spectrum disorders. While common alleles appear to play important roles in many adult diseases, our study of malformations suggested the importance of rare mutations in childhood disorders. Recently, work from many labs has suggested that childhood brain disease more broadly reflects important roles for such rare mutations.
How has the field developed since the publication of your 1999 paper?
We showed that DCX, which we had previously shown was essential for neuronal migration, binds to and regulates microtubules. Since then, the importance of microtubules in migration has been shown repeatedly. Mutations have been shown in genes encoding all of the isoforms of tubulin (from which microtubules are assembled), as well as mutations in kinesin and dynein genes.
And now we know that DCX regulates microtubule-based transport by acting as a binding “adaptor” for specific kinesins (cellular “motors” that move along the microtubules) and potentially other motors. So the genetics is leading to a dissection of the components of the neurons’ migratory “motor.”
Where would you like to see the field go from here?
Similar neuronal migration disturbances reflect mutations in genes encoding tubulin, motors and microtubule binders/motor adaptors but we lack a model for how all of these molecules come together to enable neuronal migration. The genetics gives us an unparalleled opportunity to uncover a unifying cell biology, but so far that cell biology is less clear.
What are the next big questions?
Neuronal migration disturbances give us an unusual opportunity to study a very disordered brain. What becomes of the neurons that are in the wrong place? They are known to be electrically active, can cause seizures and seem in most cases to be connected to the regular cortex. Do they participate in conscious thought or willful activity? If so, what does this say about the structure of consciousness, or about the sorts of models we generate for brain function?
Do you have any advice for scientists that are just starting out?
Find good mentors—not just good scientists but good people. Study good role models and emulate them. They define the “ecological niches” that scientists can successfully occupy. Treat your colleagues with respect. Science is a community. Embrace and advance new technology.