In mammalian embryos, brains develop from the inside out, with younger neurons moving to the outer layers in a process called radial migration. A new paper in Development finds that, during postnatal development, some of the neurons in the outer layers of the brain undergo a ‘reverse movement’, repositioning themselves by moving in the opposite direction to the initial radial migration. To learn more about the story behind the paper, we caught up with first author Juan Yang and corresponding author Xuanmao Chen, Associate Professor of Neurobiology at the University of New Hampshire (UNH), USA.
Juan Yang (left) and Xuanmao Chen (right)
Xuanmao, what questions are your lab trying to answer?
XC: We pursue three major questions. First, we investigate how ciliary signalling modulates postnatal neurodevelopment and neuronal function, thereby influencing learning and memory formation. Second, we are intrigued by how a subset of excitatory neurons in the cerebral cortex are recruited to encode and store associative memory, and how a neuronal activity hierarchy in the brain is developed and maintained. Third, inspired by our recent progress, we seek to understand the evolutionary mechanisms, other than neurogenesis, that underlie biological intelligence.
We seek to understand the evolutionary mechanisms, other than neurogenesis, that underlie biological intelligence
Juan, how did you come to work in the lab and what drives your research today?
JY: I first became interested in laboratory research during my undergraduate studies, particularly in my molecular biology class, where I was fascinated by how gene expression regulates organismal development and function. To pursue this interest, I joined the Hu lab at the Oilcrops Research Institute, Chinese Academy of Agricultural Sciences, to study how the LAZY gene regulates branching angle formation in rapeseed. I spent countless hours performing PCR for plant genotyping but genuinely enjoyed working in the lab and felt a thrill every time I saw DNA bands appear on an electrophoresis gel. After graduation, I was fortunate to obtain a technician position in the Shen lab at ShanghaiTech University, China, where I became fascinated by using cutting-edge tools, such as optogenetics and fibre photometry, to investigate how specific neural circuits control the body's homeostasis. These combined experiences sparked my passion for neuroscience and guided me to pursue my PhD dissertation research in the Chen lab at UNH, where I study neuronal primary cilia and cellular mechanisms underlying postnatal brain development.
What was known about neurodevelopment before you started the project?
JY & XC: It is well-established that pyramidal neurons in the cerebral cortex migrate from the neurogenic regions toward the cortical or hippocampal plate an inside-out manner (Cooper, 2008). Before we started the project, we had thought that pyramidal neurons only undergo unidirectional migration, and the ‘terminal translocation’ of radial migration was viewed as the final step for neuronal placement.
Can you give us the key results of the paper in a paragraph?
JY & XC: We discovered that primary cilia of early- and late-born principal neurons in compact layers in the mouse brain, such as the hippocampus CA1 region, display opposite orientations, while primary cilia of principal neurons in loose laminae, including the subiculum, entorhinal cortex, neocortex and cingulate cortex, are predominantly oriented toward the pia. However, specific cilia directionality was not observed in astrocytes and interneurons in the cerebral cortex, or in neurons in nucleated brain regions. Guided by this clue, we found that the cell bodies of principal neurons in inside-out laminated regions, including the hippocampal CA1 region and the neocortex, undergo a slow ‘reverse movement’ for postnatal positioning. Our evidence indicates that it is the reverse movement during early postnatal development that leads to the primary cilia of pyramidal neurons predominately orienting toward the pia. Therefore, the ‘terminal translocation’ of radial migration is not the last step, pyramidal neurons in the postnatal cerebral cortex continue to adjust their position and move inwards. The reverse movement must be important for constructing sparsely layered inside-out laminae and for forming sulci (grooves) in the mammalian brain.
Postnatal neuronal movement and localization. (Top) The cilia/centrioles of late-born neurons cluster at the bottom of the CA1 SP before reversing revealing the distribution pattern of cilia (red) and centrioles (green) in the CA1 SP of Arl13b+ mice. (Bottom) Reverse movement of neurons helps to form a sulcus. Ift88 cKO mice exhibit a sulcus (white arrows) in the retrosplenial cortex, which is formed by reverse movement of the neurons during postnatal development. Green arrows indicate a transition from a compact layer to a sparse and wide layer.
Postnatal neuronal movement and localization. (Top) The cilia/centrioles of late-born neurons cluster at the bottom of the CA1 SP before reversing revealing the distribution pattern of cilia (red) and centrioles (green) in the CA1 SP of Arl13b+ mice. (Bottom) Reverse movement of neurons helps to form a sulcus. Ift88 cKO mice exhibit a sulcus (white arrows) in the retrosplenial cortex, which is formed by reverse movement of the neurons during postnatal development. Green arrows indicate a transition from a compact layer to a sparse and wide layer.
What implications does your work have for understanding human brain evolution?
XC: In my opinion, the mammalian cerebral cortex, particularly the primate neocortex, can be likened to a ‘library’ consisting of numerous shelves and layers of ‘books’ (excitatory principal neurons). The development of such a sparsely layered, matrix-like architecture and its evolution from the allocortices of lower vertebrates (amphibians or reptiles) to the neocortex of humans not only involves increased neurogenesis (Florio and Huttner, 2014; Rakic, 2009; Taverna et al., 2014) and sufficient accommodating space but also requires fast, long-distance neuronal migration (Nadarajah et al., 2001) and slow, fine-tuned repositioning for final neuronal placement. These processes, in particular the slow repositioning step, permit orderly neuronal maturation and progressive circuit formation, and allow the brain to acquire external information during postnatal development to gradually construct well-organized neural circuitry to enable efficient information processing, storage and retrieval.
Upon the completion of fast radial migration, the outermost layer in the cerebral cortex is highly condensed. It is unclear how the mammalian neocortical structures gradually become loosely layered, while allocortical regions remain highly compact. I believe that an additional step of reverse movement is needed for constructing the sparse six-layered neocortex. Without reverse movement, only tightly compact three-layered laminae can be made. Without reverse movement, neuronal maturation in the hippocampal CA1 and neocortex might occur simultaneously (as occurs in the CA3 region), rather than following a sequential pattern. Therefore, the reverse movement of pyramidal neurons must be crucial for the evolutionary transition from the three-layer allocortex to six-layer neocortex. It is also linked to the gyrification process in gyrencephalic animals, because we discovered that a sulcus is formed, at least in part, via reverse movement.
Why did you choose to submit this paper to Development?
JY & XC: Development has a long-standing reputation as a leading peer-reviewed scientific journal focused on developmental biology. We rely on the editorial board's expertise in neurodevelopment and professionalism to evaluate the significance of our discoveries.
Where will this story take your lab next?
XC: This story opens multiple new avenues to explore. The lab is well positioned to address the following questions: (1) what key factors control cilia directionality and the reverse movement of principal neurons, and consequently neuronal maturation; (2) how do primary cilia regulate or stabilize neuronal positioning; (3) how can reverse movement impact the cortical evolution of mammals; and (4) how do neuronal primary cilia modulate neuronal function, contributing to associative learning and memory formation?
Finally, let's move outside the lab – what do you like to do in your spare time?
JY: I enjoy playing table games, exploring new cuisines and traveling.
XC: In the summer, I enjoy spending time with friends and family, swimming and paddling on lakes and beaches. Fall is my favourite time for hiking and admiring the vibrant maple leaves in the mountains. In winter, I love skiing with the kids. The most rewarding activity in my spare time is thinking freely without set objectives and sketching on whiteboards – a hobby that I call ‘whiteboard fun’.
College of Life Sciences and Agriculture, University of New Hampshire, Durham, NH 03824, USA.
E-mail: [email protected]
