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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
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Home | Pregnancy Timeline | News Alerts |News Archive July 30, 2014

LEFT: Diagram of the EAD region of a tapole embryo showing critical areas for brain and
facial development. RIGHT TOP: Neural crest movement RIGHT BOTTOM: Tadpole result

 






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Found, crucial path to embryo facial development

A key pathway in the formation of the front of the developing embryo gives rise to the face.

The surprising findings, reported by scientists at the Whitehead Institute of Cambridge Massachusetts, appears in the journal Cell Reports. "The results are exciting on a number of levels," says Whitehead research member Hazel Sive: "We uncovered two new and important things about facial formation and how they are linked."

In the Sive lab, the frog (Xenopus) is the animal model used to study vertebrate development. In a series of experiments, Sive concentrated on the front most portion of the developing embryo — referred to as the “extreme anterior domain” (EAD). Amanda Dickinson, a postdoctoral researcher, along with Sive found that the Wnt signaling pathway, active in a wide array of developmental processes — and in cancer, is vital for mouth formation.

They observed that frog embryos with disrupted Wnt signaling in the “extreme anterior domain” (EAD) not only failed to develop mouths, but had other facial abnormalities as well. This suggests that the EAD may act as an "organizer" or signaling center for all craniofacial regions.

Microarray analysis of EAD pointed to three genes that are also active in the Kinin-Kallikrein signaling pathway, best known in humans for regulating blood pressure, inflammation, and kidney function.

"We had no inkling this pathway was active in the embryo," says Sive.

The lab confirmed its findings through a series of experiments. In each they knocked out (turned off) one of three genes to observe the affects its loss created. Subsequent to each experiment, embryo facial regions showed significant defects ranging from no mouth, no nostrils, to abnormally small eyes. In addition, the lenghthening of the neural crest (Carnegie Stage 7), where cells give rise to nerves, cartilage, and bones, failed to occur normally.

Researchers also observed that the presence of any two of these genes produces the peptide Bradykinin. Researchers then theorized that re-introducing Bradykinin into embryos at the appropriate moment of cell division might allow the embryos to continue developing normally. Tiny beads soaked with Bradykinin peptides, were implanted in the embryos — and the surprising results were that not only frontal region formation was rescued, but proper neural crest development was also restored.

The Kinin-Kallikrein pathway ultimately produces the signaling molecule nitric oxide (NO). Not surprisingly, reduced NO levels were found in the altered embryos. Restoring normal development using peptide-soaked beads also led to an increase in NO production, further confirming the role of the pathway and its genes in facial formation.

Importantly, nitric oxide (NO) had not been thought critical for development of the EAD region.


"This study greatly enhances our overall view of craniofacial development. Knowing what tissues are communicating with each other may help us determine where we could intervene to prevent or treat developmental abnormalities of the face."

Laura Jacox, graduate student, DMD-PhD, Harvard, co-first author along with Radek Sindelka, now in Prague, Czech Republic.


It is unclear whether similar mechanisms are at play in mammals, including humans. Sive, however, believes there may be a connection. She notes that certain blood pressure medications which act on parts of the Kinin-Kallikrein pathway, can cause severe craniofacial defects in newborns if taken during pregnancy. Although such defects have been attributed to effects mediated by the kidneys, Sive's latest findings may implicate Kinin-Kallikrein signaling.

Highlights
•The Kinin-Kallikrein pathway regulates craniofacial development
•Nitric oxide regulates mouth and neural crest development
•Bradykinin stimulates nitric oxide production in the embryo
•The extreme anterior domain (EAD) attracts first arch neural crest using Cpn

Summary
The extreme anterior domain (EAD) is a conserved embryonic region that includes the presumptive mouth. We show that the Kinin-Kallikrein pathway is active in the EAD and necessary for craniofacial development in Xenopus and zebrafish. The mouth failed to form and neural crest (NC) development and migration was abnormal after loss of function (LOF) in the pathway genes kng, encoding Bradykinin (xBdk), carboxypeptidase-N (cpn), which cleaves Bradykinin, and neuronal nitric oxide synthase (nNOS). Consistent with a role for nitric oxide (NO) in face formation, endogenous NO levels declined after LOF in pathway genes, but these were restored and a normal face formed after medial implantation of xBdk-beads into LOF embryos. Facial transplants demonstrated that Cpn function from within the EAD is necessary for the migration of first arch cranial NC into the face and for promoting mouth opening. The study identifies the EAD as an essential craniofacial organizer acting through Kinin-Kallikrein signaling.


This work is supported by the National Institute of Dental and Craniofacial Research (grants 1R01 DE021109-01 and F30DE022989) Harvard University's Herschel Smith Graduate Fellowship.

Written by Matt Fearer

Hazel Sive's primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a professor of biology at Massachusetts Institute of Technology.

Full Citation: "The Extreme Anterior Domain Is an Essential Craniofacial Organizer Acting through Kinin-Kallikrein Signaling"

Cell Reports, July 17, 2014
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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