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Developmental biology - Brain

Gene Map of Brain Development

Detailed measurements of genes in individual brain cells allows scientists to trace development of the cerebellum...


Researchers at St. Jude Children's Research Hospital have created a massive database of changes in gene activity of individual mouse brain cells in the embryonic cerebellum during development and immediately after birth. This analysis of thousands of brain cells offers scientific research a high-resolution map to view the cerebellum as it wires its neural circuitry.

The research will not only aid basic understanding of brain development, but provide a foundation for cellular origins of brain disorders caused by developmental errors: anatomical defects such as Joubert syndrome, Dandy-Walker malformation and pontocerebellar hypoplasia; and, the cellular origins of childhood brain tumors such as medulloblastoma, astrocytoma and ependymoma.

Researchers can use the data via St. Jude's interface called Cell Seek. The research article appears in the journal Current Biology, and was led by co-corresponding authors John Easton PhD, , Paul Northcott PhD, and Charles Gawad MD PhD, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.

Although the cerebellum is only about 10 percent of brain volume in humans, it contains more than half of all nerve cells of our central nervous system. It also is in coordinating motor function and governing higher functions such as attention, spatial and language processing.

Easton, Northcott, Gawad and colleagues used a gene sequencing technology called single-cell RNA-seq to measure the continually changing activity of genes in single brain cells isolated from embryonic and newborn mice. Researchers sequenced RNA as its level reflects the amount of gene activity, or "expression," in a cell. RNA is the template for constructing proteins, the building blocks of cells.

Most previous brain developmental studies analyzed change in mixed brain cell types or studied a limited number of genes. However, St. Jude researchers analyzed gene expression in a vast array of genes in each cell type present in the developing mouse brain.
The scientists did RNA-seq analyses of 39,245 brain cells during 12 time points of brain development. The 12 time points - a sequence of days during brain development - were well known as stages when immature brain cells "decide" to develop into mature specialized cells.

Gawad:"What we have done is acquire global expression profiles of individual cells without using any prior knowledge. This has allowed us to study how many cell types there are at a specific development point and how they are related to each other in a much less biased manner than previous strategies. If we can capture cells in these different developmental states, we can begin to understand pediatric diseases that happen as a result of abnormal cerebellar development. Also, since most brain tumors in young children occur in the cerebellar region, this will help us identify the cells of origin for different brain tumors and brain tumor subtypes."

To demonstrate their database, the researchers traced the gene expression in a type of immature brain cell called a glutamatergic progenitor cell as it "decided" what type of mature brain cell to become. Their analysis revealed that the decision point was characterized by waves of activation of master-control genes called transcription factors that regulate other genes.

"This analysis showed us that the developmental program for these cells was even more complex than we previously appreciated," Gawad says. The finding opens the door for a deeper understanding of the type and order of genetic processes that drive these cells' maturation.
"These kinds of data would not otherwise be accessible to many labs, as they are even more complex to analyze than traditional RNA sequencing data. We wanted to build an easy-to-use interface that allowed labs without bioinformatics capability to mine the data. With Cell Seek, they can easily track the developmental processes they are interested in and use the insights to inform their experiments to study cerebellar development and disease."

Charles Gawad MD PhD, Department of Oncology and Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.

Highlights
• Single-cell transcription profiles were generated throughout cerebellar development
• Computational analyses of 39,245 cells recapitulate cerebellar development
• Lineage-based analyses discovered novel putative transcriptional regulators
• Development of Cell Seek, a web interface for studying cerebellar development

Summary
The cerebellum develops from a restricted number of cell types that precisely organize to form the circuitry that controls sensory-motor coordination and some higher-order cognitive processes. To acquire an enhanced understanding of the molecular processes that mediate cerebellar development, we performed single-cell RNA-sequencing of 39,245 murine cerebellar cells at twelve critical developmental time points. Using recognized lineage markers, we confirmed that the single-cell data accurately recapitulate cerebellar development. We then followed distinct populations from emergence through migration and differentiation, and determined the associated transcriptional cascades. After identifying key lineage commitment decisions, focused analyses uncovered waves of transcription factor expression at those branching points. Finally, we created Cell Seek, a flexible online interface that facilitates exploration of the dataset. Our study provides a transcriptional summarization of cerebellar development at single-cell resolution that will serve as a valuable resource for future investigations of cerebellar development, neurobiology, and disease.

Authors
Robert A. Carter, Laure Bihannic, Celeste Rosencrance, Jennifer L. Hadley, Yiai Tong, Timothy N. Phoenix, Sivaraman Natarajan, John Easton, Paul A. Northcott, Charles Gawad.


Acknowledgements
Other St. Jude researchers are already using Cell Seek in their studies of both normal development and childhood cancer formation.

The research was funded by the V Foundation, the Sontag Foundation; the Alexander and Margaret Stewart Trust; the American Association for Cancer Research; the Burroughs Wellcome Fund; the Hyundai Pediatric Cancer Foundation; the Leukemia and Lymphoma Society; and ALSAC, the fundraising and awareness organization of St. Jude.

P.A.N. is the recipient of a V Foundation V Scholar Award and a Sontag Foundation Distinguished Scientist Award, and is a Pew-Stewart Scholar for Cancer Research (Alexander and Margaret Stewart Trust). P.A.N. acknowledges additional funding support from the American Association for Cancer Research (NextGen Grant for Transformative Cancer Research) and ALSAC. C.G. is also supported by funding from the Burroughs Wellcome Fund, Hyundai Pediatric Cancer Foundation, Leukemia and Lymphoma Society, and ALSAC. We thank Brandon Stelter (Biomedical Communications, St. Jude Children’s Research Hospital) for assistance with artwork. We thank Drs. Kathy Millen and Kim Aldinger from Seattle Children’s Hospital for critically evaluating the manuscript.

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Sep 18, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




(A) Schematic of mouse cerebellar development highlighting time points used and 'birthdates' of major neuronal cell types. (B) Illustration of the experimental workflow. Image: St. Jude Children's Research.


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