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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 communicate with rhythm and beat

Cells communicate dynamically using pulsed molecular signals delivered at differing rates of speed over time...

Multicellular organisms like ourselves need a constant flow of information between millions of cells, coordinating their activities so they can proliferate more of the same cells or differentiate into new tissues. Deciphering the language of this communication system has been a challenge in biology for a long time. Now, California Institute of Technology (Caltech) scientists have discovered that cells transmit messages through a single pathway, or communication channel, by encoding messages rhythmically over time.

The work, conducted in the laboratory of Michael Elowitz, professor of biology and bioengineering, Howard Hughes Medical Institute Investigator, and executive officer for Biological Engineering, is described in a paper in the February 8 issue of Cell.
In particular, the scientists studied a key communication system called Notch used in nearly every tissue within animals. Malfunctions in the Notch pathway contribute to a variety of cancers and developmental diseases, making it a desirable target to study for drug development.

The "Notch" pathway facilitates communication between neighboring cells using molecules from one cell to the surface of another to be sent into the nucleus of that cell to activate or deactivate genes. Cells constantly send messages such as: divide into an identical cell or differentiate into a new kind of cell in the developing fetus, or repair injury in a child or adult.
The Notch Pathway

(1) Notch triggers specialized molecules called ligands to form on the surface of a sending cell.

(2) Ligands touch and modify molecular antennae or ligand receptors on adjacent, receiving cells.

(3) Transcription factors are then released inside the cell to enter the nucleus.

(4) In the nucleus transcription factors activate specific genes on DNA.

Because all ligands prompt modification of receptors on a receiving cell to activate transcription factors in the same way, scientists generally assumed the receiving cell did not spend energy to determine which ligand activated it, or which message was received. Lead author Nagarajan Nandagopal PhD explains: "All evidence so far suggests that, unlike mobile phones or radios, cells have much more trouble precisely analyzing incoming signals. They are usually excellent at distinguishing between the presence or absence of signal, but not very much more...[it was assumed] cellular messaging is closer to sending smoke signals than texting."

Nandagopal and collaborators wondered whether an explanation for how cells distinguish between two ligands, if they did at all, was in the timing of Notch activation by different ligands or how this "smoke signal" is emitted over time. So, they developed a video-based system to record cell signaling from cell to cell and in real time, by tagging receptors and ligands with fluorescent protein markers. Now, the team could watch molecules interact as signaling occurred.
Capturing the signalling of two chemically similar Notch ligands, Delta1 and Delta4, scientists calculated the activation of their receptor ligands:

Delta1 ligands activated clusters of receptors all at once, sending a sudden burst of transcription factors to the nucleus simultaneously.

Delta4 ligands activated individual receptors with a steady pulse, sending a sustained stream of single transcription factors to the nucleus.

These two patterns encoded different instructions to the cell in a mechanism enabling the two ligands to communicate dramatically different messages. By analyzing chick embryos, the authors discovered:

Delta1 activated abdominal muscle production, however,

Delta4 strongly inhibited that process in the same cells.

Elowitz: "Cells speak only a handful of different molecular languages but they have to work together to carry out an incredible diversity of tasks. We've generally assumed these languages are extremely simple, and cells can basically only grunt at each other. By watching cells in the process of communicating, we can see that these languages are more sophisticated and have a larger vocabulary than we ever thought. And this is probably just the tip of an iceberg for intercellular communication."

Dll1 and Dll4 can activate distinct targets through the same Notch receptor
Ligand identity is encoded in pulsatile or sustained Notch activation dynamics
Dynamic encoding involves ligand-receptor clustering
Dll1 and Dll4 induce opposite cell fates during embryonic myogenesis

The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency-modulated pulses that specifically upregulate the Notch target gene Hes1. By contrast, Dll4 activates Notch1 in a sustained, amplitude-modulated manner that predominantly upregulates Hey1 and HeyL. Ectopic expression of Dll1 or Dll4 in chick neural crest produced opposite effects on myogenic differentiation, showing that ligand discrimination can occur in vivo. Finally, analysis of chimeric ligands suggests that ligand-receptor clustering underlies dynamic encoding of ligand identity. The ability of the pathway to utilize ligands as distinct communication channels has implications for diverse Notch-dependent processes.

Authors: Nagarajan Nandagopal, Leah A. Santat, Lauren LeBon, David Sprinzak, Marianne E. Bronner, Michael B. Elowitz, Albert Billings.

Funding was provided by the Defense Advanced Research Projects Agency, the National Institutes of Health, the National Science Foundation, and the Howard Hughes Medical Institute.

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Feb 21, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

(LEFT) Artist rendering of a cell expressing the Delta1 ligand - in clusters and (RIGHT) a cell expressing the Delta4 ligand - in a steady stream. The two ligands activate cell receptors in the same way. But, by producing different dispersal rates over time, send different instructions. Image credit: CalTech

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