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Developmental biology - Neural Functions

You Are What Your Mother Eats

Research finds link between a mother's diet and infant growth...

For years, pregnant mothers have questioned their nutritional habits: "Will eating more cause my baby to be overweight?" Or, "I'm eating for two, so it won't hurt to have an extra serving, right?"

Many factors, such as the age of the mother, her overall health and genetics ultimately play a role in correlations between a mom's nutrition habits and her metabolism. But, it has been proved her diet directly impacts the growth of her child. And researchers at OHSU in Portland, Oregon, believe they may be one step closer to knowing why.

In a study published online in Nature Communications, the research team, led by Jae W. Lee PhD, has demonstrated how two neurons that are key to growth and metabolism - GHRH (growth hormone-release hormone) and AgRP (Agouti-related peptide) - are also developmentally interconnected.

Hypothalamic leptin-melanocortin pathway

Located in the hypothalamus region of the brain, within a group of neurons known as the arcuate nucleus, GHRH neurons orchestrate body growth and maturation. Meanwhile, AgRP neurons stimulate feeding and suppress energy usage.

To understand how these neurons are developed, the research team cataloged various proteins expressed in the arcuate nucleus of mice and analyzed their overall function.
"We found that one specific protein called DLX1 is critical for GHRH neuron development. However, it also suppresses development of the AgRP neuron. When DLX1 was removed, the mouse's growth was stunted, and it appears obese."

Jae W. Lee PhD, Professor of Pediatrics, OHSU School of Medicine, and OHSU Doernbecher Children's Hospital.

Additionally, DLX1 was found to suppress the development of OTP-labeled cells that become AgRP neurons. This would suggest normal growth development, but limited blockage of energy use, results in a trim figure.

"For the first time, these findings prove the intimate relationship between GHRH and AgRP neurons in developmental lineage. Further, the development of both neurons can be artificially preset in controlling postnatal growth," Lee said.

The researchers now are working to determine if DLX1 may be controlled by diet. By testing both high-fat and low-protein - or malnourished - diets in mice, Lee hopes to identify how food impacts a baby's genetic makeup in the womb. This could scientifically support the idea that 'you are what your mother eats.'

Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.

Authors: Bora Lee, Janghyun Kim, Taekyeong An, Sangsoo Kim, Esha M. Patel, Jacob Raber, Soo-Kyung Lee, Seunghee Lee and Jae W. Lee

Data availability
Dlx1 ChIPseq data that support the findings of this study have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) and are accessible through the GEO Series accession number GSE104372. All other relevant data are available from the corresponding author on request.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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May 28, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Dwarfism in Dlx1/2cKO male mouse with verification of his linear body length, weight, IGF1 expression, liver (qRT-PCR) and serum glucose levels, relative to his littermate as control.
Image credit: Jae W. Lee PhD, Doernbecher Children's Hospital

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