In a study published in the journal Cell, research teams have uncovered key genes that guide the process of brain development.
Why do certain brain cells connect to one area while specifically avoiding other, nearby cells? Understanding how brain cells in the hypothalamus form these specific, complex connections - and how this process can be adversely affected - could provide insight into the development of childhood obesity.
Researchers identified a group of molecules called semaphorins, which are found in abundance in the developing hypothalamus. Brain cells release semaphorins to communicate with other brain cells. These messages act as a sort of road map, guiding cells towards or away from other cells. But what happens to the brain when that road map is no longer functioning properly?
They blocked semaphorin signaling in cells of the hypothalamus and discovered that brain cells no longer grew the way they were supposed to, showing that semaphorin provides an essential map for them to follow. In addition to connections failing to establish, loss of semaphorin action in a preclinical model also caused elevated body weight. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. "What we are seeing is that semaphorins are guiding and shaping development of hypothalamic circuits that ultimately regulate calorie intake," explains the co-senior author.
Another team tested 1,000 DNA samples and found that individuals with early-onset obesity had more rare mutations in genes involved in semaphorin signaling than healthy individuals. Authors found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. The finding that people with obesity have rare mutations in semaphorin signaling shows that semaphorins are important in maintaining healthy body weight.
In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis.
"We have now discovered the genes that establish the precise neural connections that form these circuits," says co-first author on the paper. "This work provides new insights into the development of hypothalamic circuits that regulate appetite and metabolism."
This multifaceted study reveals a much clearer picture of what occurs in the developing brain. Semaphorin signaling appears to shape the physical architecture of the brain and influence circuitry governing body weight.
How genes involved in neural development can affect body weight
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