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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Cells send out stop/go signals to extend nerves

Molecular signals sent across great distances make neurons extend and contract axon growth and knit together our nervous system.

How do millions of neurons manage to connect with their target cells and mature into our nervous system? Particularly given their limited guidance cues. Max Planck scientists have found navigating axons respond to a balance of positive and negative cues to advance neurons. Their genetic studies in the upper hindlimbs of mice, have unravelled how repellent ephrin proteins cooperate and guide motor axons.

Ephrins, or eph receptors, are a family of proteins that bind biomolecules together. Eph receptors make up the largest known protein-tyrosine kinases (PTKs) — or high-affinity cell surface receptors — which bind and activate many growth factors, cytokines, and hormones. A deficiency in cytokine receptors is directly linked to certain immunodeficiency diseases, while hormones signal molecules that regulate our physiology and behavior. Eph receptors and their partner proteins, ephrins, are anchored to a cell's membrane and represent an intercellular communication system engaging in cell–cell contact, sending out bidirectional signals vital to intercellular communication.

Upon contact, Eph–expressing axons move away from ephrin-expressing cells. Ephrins do the same. Eph/ephrin signals can even be bi-directional, with the Eph receptor (forward signaling) and ephrin (reverse signaling). Eph forward signaling, in most cases causes cell repulsion, while ephrin reverse signaling can be an attractant or adhesive between cells. In the developing brain, these two opposing forces guide young neurons to the right partner cell. Each plays an important role in cell migration, regeneration, neurodegenerative disease, and sometimes the development of cancers.

Until recently, scientists assumed these signal transmissions only occured through direct cell-cell contact. Now, the Max Planck team led by Rüdiger Klein PhD, shows cells can also pack ephrin/Eph receptors in extracellular vesicles. This discovery improves our knowledge of one type of cell communication system, and may pave the way for new therapy strategies in mis-communications.

The work is published in the Journal of Cell Biology.

The ephrin-Eph system is found on the surface of almost all cell types. After an ephrin meets the Eph receptor on another cell, they join to form an ephrin/Eph-receptor complex — one or both of these cells then incorporates that complex internally and repulses away the other cell.

The repelled cell is thus pushed to grow in a new direction. These interactions occur over and over in the nervous system, extending young neurons.

Ephrin/Eph receptors were also found in extracellular vesicles or exosomes (small fat droplets) released by cells,"... brings up the interesting question of what business do Ephs and ephrins have in exosomes?," added Klein.

Intrigued, the team set up an elaborate experiment purifying exosomes of different cell types. Analysis of exosome contents revealed many contain ephrins/Ephs. This helped to decode exosomes' ephrin/Eph cellular mechanism. Eph receptors were not being dumped as waste products in exosomes, but were active in exosomes as receptors binding ephrin molecules to growing neurons — and repelling neuronal extensions.

Ephrins and Eph receptors were also found in exosomes of cancer cells.

"This might mean that strategies to control exosome release could be used to interrupt the ephrin-Eph signaling pathway and thereby disrupt tumour growth."

Rüdiger Klein PhD, Max Planck Institute of Neurobiology and Biochemistry, Martinsried, Germany, and the Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that ephrin-Eph signaling requires direct cell contact. Although the biological functions of ephrin-Eph signaling are well understood, our mechanistic understanding remains modest. Here we report the release of EVs containing Ephs and ephrins by different cell types, a process requiring endosomal sorting complex required for transport (ESCRT) activity and regulated by neuronal activity. Treatment of cells with purified EphB2+ EVs induces ephrinB1 reverse signaling and causes neuronal axon repulsion. These results indicate a novel mechanism of ephrin-Eph signaling independent of direct cell contact and proteolytic cleavage and suggest the participation of EphB2+ EVs in neural development and synapse physiology.

Submitted: 25 January 2016

Original publication: Jingyi Gong, Roman Körner, Louise Gaitanos, Rüdiger Klein; Exosomes mediate cell contact-independent ephrin-Eph signaling during axon guidance. Published June 27, 2016 // JCB vol. 214 no. 1 35-44

The Rockefeller University Press, doi: 10.1083/jcb.201601085
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White fat begins to be made

A motor axon growth cone (GREEN) approaches a cell expressing an ephrin (red).
Image Credit: MPI of Neurobiology / Rüdiger Klein



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