This week we profile a recent publication in Science from the laboratory of
Dr. Kathleen Millen (pictured, center) at Seattle Children’s Research Institute.
Can you provide a brief overview of your lab’s current research focus?
We study the developmental basis of human neurodevelopmental disorders – including intellectual disability, autism, epilepsy and structural brain birth defects.
What is the significance of the findings in this publication?
We have conducted the first-ever histological and molecular analyses of the developing human cerebellum, and found that there are many stark differences in developmental patterns between the mouse and human cerebellum. For example, we find that the two main progenitor zones that give rise to all cerebellar neurons are expanded structurally in humans to include a subventricular zone. Moreover, these expanded zones, like in the cerebral cortex, contain an additional class of progenitors, namely outer radial glia-like basal progenitors. These cerebellar progenitors have never been described in any other vertebrate.
Of particular significance is the development of the dorsal stem cell zone called the rhombic lip. The rhombic lip is the primary source of cerebellar granule neurons – the most abundant class of neurons in the brain, comprising 80% of all of the neurons in the human brain. In mice, the rhombic lip is extremely short-lived and disappears before key phases of cerebellar growth and foliation. In humans, we find that rhombic lip development is protracted and it is present throughout gestation, including during the 3rd trimester when human cerebellar volume increases 5-fold. This temporal persistence of the rhombic lip is not seen in the mouse or even non-human primates like the monkey, suggesting this feature is likely human-specific. Our additional analysis of samples with cerebellar malformations suggests that the elaborate human rhombic lip is involved in the growth and maintenance of the posterior cerebellum, a region of the cerebellum that has been associated with human cognition.
Our findings significantly change how we believe some human cerebellar developmental disorders occur. For many decades, the scientific community has used mice to define the underlying developmental disruptions that lead to human cerebellar birth defects. While many features of cerebellar development are conserved and mice have provided many answers, several human cerebellar birth defects have been difficult to model. This includes Dandy-Walker malformation and some groups of medulloblastoma – the most common malignant brain cancer in children. It is now clear that the underlying pathological mechanisms of some disorders can never be fully modeled in mice, because mice lack critically important transient developmental zones seen in humans. Our studies underline that human developmental studies are essential to define human biology.
What are the next steps for this research?
We are working very hard to describe the developmental programs of the newly identified cerebellar progenitors, defining their molecular signatures, the signaling pathways that influence them, and of course, how these progenitors proliferate, migrate and differentiate to build the human cerebellum. We expect that this information will provide new insights into the underlying causes of human cerebellar neurodevelopmental disorders, including medulloblastoma, which we can leverage to provide better diagnostic information and perhaps eventual new therapies.
This work was funded by:
This work was supported by NIH-R01-NS080390 and R01-NS095733 to KJM and R01-N5050375 to WBD. PH was awarded EMBO fellowship: ATSF-431-2016, Burroughs-Wellcome Fund:1018771, Company of Biologists Fellowship:DEVTF190393 and National Ataxia Foundation Young Investigator Research Grant. PA was awarded the Newlife Charity for disabled children Start-Up Grant:SG/17-18/05.
