Demystifying a mammal’s brain, cell by cell

In collaboration with scientists at the Allen Institute for Brain Science, Zhuang and her team used MERFISH together with single-cell RNA sequencing data to not only identify each cell type, but to image them in situ. Their work provides new information about the molecular signatures of these cell types, as well as where they are located in the brain. The result is a stunningly detailed picture of the mouse brain’s full complement of cells, their gene-expression activity, and their spatial relationships.

In their Nature paper, the researchers used MERFISH to determine gene-expression profiles of approximately 10 million cells by imaging a panel of 1,100 genes, selected using single-cell RNA sequencing data provided by Allen Institute collaborators.

Retina findings could boost glaucoma research

In a separate paper in the Nature series, Joshua Sanes, the Jeff C. Tarr Professor of Molecular and Cellular Biology, co-led a team that captured new insights into the evolutionary history of the vertebrate retina.

A part of the brain encased in the eye, the retina boasts complex neural circuits that receive visual information, which they then transmit to the rest of the brain for further processing. The retina is functionally very different from species to species — for example, human hunter-gatherers evolved sharp daytime vision, whereas mice possess better night vision than humans do; some animals see in color, while others see predominantly in black and white.

But at molecular levels, how different are retinas, really? Sanes, in collaboration with researchers at the University of California, Berkeley, and the Broad Institute, performed a new comparative analysis of retinal cell types across 17 species, including humans, fish, mice, and opossums. Using single-cell RNA sequencing, which allowed them to differentiate types of retinal cells by their genetic expression profiles, the researchers’ findings upended some long-held views about how certain species’ visual systems evolved.

One striking discovery involved so-called “midget retinal ganglion cells,” which, in humans, carry 90 percent of the information from the eye to the brain. These cells give humans their fine-detail vision, and changes to them are associated with eye diseases such as glaucoma. No related cells had ever been found in mice, so they had been assumed to be unique to primates.

In their analysis, Sanes and team identified for the first time clear relatives of midget retinal ganglion cells in many other species, including mice, albeit in much smaller proportions. Since mice are a common model animal to study glaucoma, being able to pinpoint these cells is a potentially crucial insight.

“I think we can make a very compelling case that if you want to study these important human retinal ganglion cells in a mouse, these are the cells you want to be studying,” Sanes said.

Other Harvard-affiliated researchers, at Harvard Medical School, Boston Children’s Hospital, and the Broad, also contributed findings to the NIH’s cell census network, including a molecular cytoarchitecture of the adult mouse brain, and a transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.