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Developmental Biology - Brain

The Body's Weight Center Is In The Brain

Maintaining proper weight is a complex brain activity...


Leading a unique, collaborative research study with scientists across the globe, investigators at the University of Cambridge and Children's Hospital Los Angeles (CHLA) have pinpointed a set of molecules that wire the body weight center of the brain.

In a study published January 17th in the journal Cell, Sadaf Farooqi PhD, FRCP, FMedSci, of the University of Cambridge and CHLA's Sebastien Bouret, PhD led research teams to uncover key genes that guide the process of brain development.

"We know that the brain, in particular an area called the hypothalamus, has a very important role in the regulation of food intake and blood sugar," explains Bouret, who is also an associate professor of pediatrics at the Keck School of Medicine of USC. Researchers have focused on the hypothalamus for years in an effort to study the epidemic of obesity, which affects nearly 14 million children and adolescents in the United States. "What we don't yet understand," he says, "is how these circuits in the hypothalamus are being organized. We want to know how the brain puts itself together and what exactly governs that process." Understanding this is key because circuits must be established properly in order for the brain to ultimately perform complex functions like maintaining proper weight.

Why do certain brain cells connect to one area while specifically avoiding other, nearby cells? Bouret's laboratory investigates how this precise wiring is achieved. 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.

Bouret studied 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?

Dr. Sophie Croizier, who led the study in Bouret's lab, blocked semaphorin signaling in cells of the hypothalamus, discovering that brain cells no longer grew the way they were supposed to. This showed that semaphorin provides an essential map for neurons to follow. In addition to connections failing to establish, loss of semaphorin signals in a preclinical model also caused elevated body weight. "What we are seeing is that semaphorins are guiding and shaping development of hypothalamic circuits that ultimately regulate calorie intake," explains Bouret.

But the story does not stop here.

Professor Farooqi from the University of Cambridge also analyzed genetic information from individuals with obesity. Farooqi's team tested 1,000 DNA samples to find individuals with early-onset obesity had more rare mutations in genes involved in semaphorin signaling than healthy individuals. The finding that people with obesity have rare mutations in semaphorin signaling shows that semaphorins are important in maintaining healthy body weight.

"We have now discovered the genes that establish the precise neural connections that form these circuits," says Dr. Agatha van der Klaauw, who led the study in Farooqi's lab and is 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.

Summary
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we 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. 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. 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. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

Highlights
• Rare variants affecting Semaphorin 3 signaling are associated with human obesity
• Disruption of Semaphorin 3 signaling leads to weight gain in zebrafish and mice
• Semaphorin 3 signaling promotes the development of hypothalamic melanocortin circuits

Authors
Agatha A. van der Klaauw, Sophie Croizier, Edson Mendes de Oliveira, Lukas K.J. Stadler, Soyoung Park, Youxin Kong, Matthew C. Banton, Panna Tandon, Audrey E. Hendricks, Julia M. Keogh, Susanna E. Riley, Sofia Papadia, Elana Henning, Rebecca Bounds, Elena G. Bochukova, Vanisha Mistry, Stephen O’Rahilly,Richard B. Simerly, INTERVAL, UK10K Consortium, James E.N. Minchin, Inęs Barroso, E. Yvonne Jones, Sebastien G. Bouret and I. Sadaf Farooqi Authors on the study are: co-first author Sophie Croizier and Soyoung Park, both of the Saban Research Institute of CHLA: Edson Mendes de Oliveira, Lukas K.J. Stadler, Matthew C. Banton, Julia M. Keogh, Sofia Papadia, Elana Henning, Rebecca Bounds, Elena G. Bochukova, Vanisha Mistry, Stephen O'Rahilly, and Inęs Barroso, all of the University of Cambridge; Richard Simerly, of Vanderbilt University; Youxin Kong and E. Yvonne Jones, of the University of Oxford; Panna Tandon, Susanna E. Riley, and James E. N. Minchin of the University of Edinburgh; Audrey E. Hendricks of the Wellcome Sanger Institute in Cambridge and the University of Colorado.

Acknowledgements
Studies in humans were supported by Wellcome (AAvdK; IB, ISF; 099038/Z/12/Z; 098497/Z/12/Z; WT098051), the Medical Research Council (MRC) (ISF, SOR; MRC_MC_UU_12012/5), the National Institute of Health Research (NIHR), Cambridge Biomedical Research Centre (ISF, IB, SOR), and the Bernard Wolfe Health Neuroscience Endowment (ISF). E.M.d.O. was supported by the Brazilian National Council for Scientific and Technological Development - CNPq (233690/2014-0). J.E.N.M. was supported by a joint University of Edinburgh and British Heart Foundation (BHF) Centre of Research Excellence Fellowship. S.G.B. was supported by the NIH (DK84142, DK102780, and DK118401).

Structural analysis was performed by Y.K. and E.Y.J., who are supported by Cancer Research UK and the UK MRC (C375/A17721 and MR/M000141/1 to E.Y.J.) and Wellcome (203141/Z/16/Z, supporting the Wellcome Centre for Human Genetics). Whole-exome sequencing was performed as part of the UK10K consortium (a full list of investigators who contributed to the generation of the data is available from https://www.uk10k.org/). Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (https://www.nhsbt.nhs.uk/), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the NIHR, the NIHR BioResource (https://bioresource.nihr.ac.uk/), and the NIHR Cambridge Biomedical Research Centre (www.cambridgebrc.nihr.org.uk/).

The academic coordinating center for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK MRC (MR/L003120/1), BHF (RG/13/13/30194), and NIHR Cambridge BRC. A complete list of the investigators and contributors to the INTERVAL trial is provided (Moore et al., 2014). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We are indebted to the participants and their families for their participation and to the Physicians involved in the Genetics of Obesity Study (GOOS). We acknowledge the Wellcome-MRC Institute of Metabolic Science (IMS) Translational Research Facility (TRF) and Imaging Core Facility, both of which are supported by a Wellcome Strategic Award (100574/Z/12/Z).

We thank the Rodent Metabolic Core and Cellular Imaging Core of CHLA. We thank Joshua H. Cook for his expert technical assistance, Dr. Olivier Kah for neuroanatomical advice in zebrafish, and Gricelda Vasquez for animal husbandry.

The authors declare no competing interests.

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Jan 23, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Long, wire-like projections of neurons in the hypothalamus form our body weight circuits (red/green). Cell bodies from one area of the hypothalamus (bottom) branch up to another. These cells specifically avoid some areas (dark) to reach proper targets. Image: Dr. Sebastien Bouret, CHLA.


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