Baltimore, MD, USA. A research team has generated the first comprehensive genetic parts list of a mouse hypothalamus, an enigmatic region of the brain that links the central nervous system to control of hormone levels.

The hypothalamus is one of the most diverse and complex parts of the brain, composed of at least dozens — more likely many hundreds — of different types of neurons. Each neuron type corresponds to a specific gene that has remained unidentified until now. Looked at visually, the cellular arrangement within the hypothalamus more closely resembles a bowl of spaghetti than a neatly organized club sandwich.

The catalog of molecular markers now identified helps to unravel this complexity. The index of the genes involved in producing its many cell types is a toolbox that researchers can use to manipulate the activity of brain cells by turning them on and off, or by tracing their connections. Knowing how cells develop in this part of the brain help scientists understand of how they regulate behavior, mood and metabolism.

Hypothalamus. A diagram of the developing mouse brain showing the hypothalamus.

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We already know that the hypothalamus controls hunger, thirst, fatigue, body temperature, and wake-sleep cycles. Developmental flaws may underlie both inborn and acquired metabolic balance problems that can lead to mood disorders, high blood pressure, obesity, and diabetes.

Seth Blackshaw, Ph.D., is an assistant professor in the Department of Neuroscience at the Johns Hopkins University School of Medicine. Blackshaw and his colleagues in the United States and Japan published their new report in Nature Neuroscience.

"The study of hypothalamic development, particularly of cell specification, will help us to understand how hypothalamic neurons function to regulate behavior and physiology," says Blackshaw. "Because of when and where we saw certain genes turn on, we now have identified a set of candidate players that guide the assembly of the different parts of the hypothalamus and that specify the many individual cell types within it."

The team's first challenge was to dissect away, at the very start of neural development, the part of the mouse brain which develops into the hypothalamus, and then cut tiny slices of this region for use in microarray analysis, a technology that reveals multiple gene activity. By analyzing all the roughly 20,000 genes in the mouse genome, the team identified 1200 as strongly activated in developing hypothalamus and characterized the cells within the hypothalamus in which they were activated.

The team then characterized the expression of the most interesting 350 genes in detail using another gene called Shh (for sonic hedgehog) as a landmark to identify the precise region of the hypothalamus in which these genes were turned on. This involved processing close to 20,000 tissue sections — painstakingly sliced at one-fiftieth of a millimeter thickness and then individually examined.

"We were able to use this data to find genes whose expression matched every individual hypothalamic nucleus and essentially assemble a jigsaw puzzle of gene expression patterns that completely covered the developing hypothalamus," Blackshaw says.

"Now that we have a complete set of molecular landmarks, along with an extensive molecular parts list, we can begin to learn how all these parts fit together to create this essential and highly complex brain region."

This may ultimately lead to better diagnostic and treatment options for a variety of disorders.

CitationA genomic atlas of mouse hypothalamic development. Tomomi Shimogori, Daniel A Lee, Ana Miranda-Angulo, Yanqin Yang, Hong Wang, Lizhi Jiang, Aya C Yoshida, Ayane Kataoka, Hiromi Mashiko, Marina Avetisyan, Lixin Qi, Jiang Qian, Seth Blackshaw. Nature Neuroscience 2010; 13(6): 767-775. doi:10.1038/nn.2545

Abstract

The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.

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TS-Si is dedicated to the acceptance, medical treatment, and legal protection of individuals correcting the misalignment of their brains and their anatomical sex, while supporting their transition into society as hormonally reconstituted and surgically corrected citizens.

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