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Mouse Transcriptome Study Offers Window into Developing Mammalian Brain

NEW YORK (GenomeWeb News) – Mammalian brain development involves the coordinated expression of a host of genes — including many transcriptional regulators, according to a study comparing the mouse cortex transcriptomes at two early developmental stages.

In a paper scheduled to appear online this week in the Proceedings of the National Academy of Sciences, a team of American and Chinese scientists used single and paired-end Illumina sequencing to characterize the messenger RNAs in the cortices of mouse embryos and post-natal mice. The researchers detected transcripts representing more than 16,000 genes, including nearly 3,800 whose expression varied between the two developmental stages.

"This differential activity tells us about the differences in the brain at these two stages," senior author Hong Ma, a researcher affiliated with Pennsylvania State University and Shanghai's Fudan University, said in a statement. He and his co-authors noted that the current results "pave the way for further functional analysis of a large number of genes in the early developing brain."

Although microarray and other studies have provided some insights into the changes that occur within the mammalian brain during development, many of the intricacies of this early brain development remain unknown.

In an effort to better understand this process, Ma and his colleagues decided to compare the transcriptomes of cells from the cortex of mouse embryos and post-natal mice — research that they say could ultimately improve researchers' understanding of human brain development and function as well.

"Since many psychiatric disorders such as autism and mental retardation are closely associated with early brain development, understanding the gene expression profile will facilitate the search for an optimal treatment for these disorders," the authors argued.

The team used Illumina sequencing to assess cDNA libraries made from mRNAs in the cortices of between five and eight 18-day-old mouse embryos (dubbed "E18") or seven-day-old mouse pups ("post-natal" or "P7"). The same samples were assessed using both single- and paired-end sequencing reads.

"Brain development in an 18-day-old embryo involves a significant amount of brain cells, or neurons," Ma said in a statement. "In contrast, brain development in a seven-day-old infant involves the formation of numerous connections between these neurons."

Using this approach, the researchers generated millions of single- and paired-end reads from the E18 and P7 cortices. Nearly 61 percent of the single reads and almost 52 percent of paired reads uniquely mapped to the genome, allowing the team to detect transcripts representing 16,083 different genes.

Of these, 14,787 were detected in E18 and 15,423 were detected in P7. Many, but not all, of the transcripts mapped to known genes, the researchers noted: others mapped to intronic and intergenic regions of the mouse genome.

The group's analyses also turned up more than 4,000 alternatively spliced transcripts. More than half of these were found in only one of the two developmental stages, the authors noted, indicating "substantial variation between [two] developmental stages of the same tissue."

When they compared the cortical gene expression at each stage, the researchers found that genes involved in processes such as energy production and microtubule function were highly expressed at both stages. Transcription factors also seemed to be quite common in the cortices of both embryos and young pups, leading the team to speculate that "transcriptional regulation plays a prominent role during a critical window of brain circuit formation."

But some genes had very different expression from one developmental stage to the next. The researchers noted that 3,758 were differentially expressed in each of the two developmental stages, even after weeding out thousands of differentially expressed transcripts using stringent statistical analyses. And more than 5,800 genes showed moderate expression differences between the two developmental stages.

For instance, genes that have been previously implicated in neurogenesis — such as the transcription factor genes Sox4 and Sox11 — were detected at higher levels in the embryonic stage than the post-natal stage, the researchers found. On the other hand, the post-natal mouse cortexes had higher levels of genes coding for synaptic proteins involved in transmitting signals between neurons.

Among the transcripts detected in the mouse embryos and post-natal mice were those corresponding to human genes involved in neurological diseases such as Alzheimer's, mental retardation, seizure disorders, and autism, suggesting the genes have yet-undetermined roles in early brain development.

"Our results can help to pinpoint the specific time during brain development when the genes related to certain diseases are active," Ma said. "This knowledge may help other scientists to develop drugs or gene therapies that can treat the diseases."

Down the road, the researchers reportedly plan to hone in on some of the genes that appear to be expressed in the embryonic and/or post-natal mouse cortex to determine what roles, if any, they have in brain function and formation.

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