ScienceDaily (June 10, 2010) — A Johns Hopkins and Japanese research team has generated the first comprehensive genetic "parts" list of a mouse hypothalamus, an enigmatic region of the brain -- roughly cherry-sized, in humans -- that controls hunger, thirst, fatigue, body temperature, wake-sleep cycles and links the central nervous system to control of hormone levels.
A. A diagram of the developing mouse brain at 12 days gestation. The hypothalamus is outlined in red, while cells that express the Shh gene, which was used as a landmark in this study, are shown in brown. B. Various different genes that are turned on in different parts of the hypothalamus are shown in purple, while Shh is shown in brown. (Credit: Image courtesy of Johns Hopkins Medical Institutions)
Flaws in hypothalamus development may underlie both inborn and acquired metabolic balance problems that can lead to obesity, diabetes, mood disorders and high blood pressure, according to a report on the study published May 2 in the advance online publication of Nature Neuroscience.
"Knowing how cells develop in this part of the brain will help us understand how they regulate behavior, mood and metabolism," says Seth Blackshaw, Ph.D., an assistant professor in the Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine.
The hypothalamus is one of the most diverse and complex parts of the brain, and having an 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 tracing their connections. This may ultimately lead to better diagnostic and treatment options for a variety of disorders.
"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."
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A 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
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Nature Neuroscience 13, 767–775 (2010) doi:10.1038/nn.2545Received 21 January 2010 Accepted 11 March 2010 Published online 02 May 2010
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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