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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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Developmental Biology - Stem Cells

How Stem Cells Lose Their Unlimited Potential

Researchers discover how cells identify their future and forget their past...

Stem cells all share the potential of developing into any specific cell in the body. Many researchers therefore try to answer this fundamental question:

(1) What determines a stem cells' developmental fate?
(2) When/why they lose potential to become any cell type.

Now, researchers from the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) at the University of Copenhagen have discovered how stem cells can lose this potential and thus can be said to "forget their past".

It turns out that proteins called transcription factors play a role scientists had not identified. For 30 years, the dogma has been:

"Transcription factors are engines of gene expression,
triggering genes to switch 'on' or 'off'

However, new research published in Nature reveals something quite different.

"We previously thought transcription factors drove the process determining whether a gene is expressed [functioning] and subsequently translated into a corresponding protein.

Our new results show that transcription factors may be more analogous to being the memory of a cell. As long as transcription factors are connected to a gene, that gene can be read [turned on].

However, external signals seem to determine whether a gene is turned on or off. As soon as transcription factors are gone, cells cannot return to their point of origin."

Joshua M. Brickman PhD, Professor and Group Leader, The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark.

How a cell slowly develops from one state to another is key to understanding cell behavior in multi-cellular organisms. Stem cell researchers are constantly trying to refine techniques to develop stem cells into various specific cell types to be used, for example, in regenerating the damaged tissue of major organs.

So far, however, making all cells in a dish do the same thing at the same time has been extremely difficult.

A Protein Centered Viewpoint

So, researchers developed a stem cell model to mimic a cell's response to signals. Using it, for the first time, to precisely determine the sequence of events in a gene being turned on and off in response to a signal. Now, they are able to describe under what circumstances a cell may develop along one pattern — and then return to its starting-point.

Part of this discovery involved measuring how proteins in a cell are modified by phosphorylation by using advanced mass spectrometry available through an important collaboration with Jesper Olsen's Group at the Novo Nordisk Foundation Center for Protein Research (CPR).
"Combining forces with the Olsen group in the CPR enabled us to provide a unique deep description of how individual proteins in a cell react to signals from the outside."

Joshua M. Brickman PhD.

New Answers to Old Scientific Questions

The results are surprising. Although the sequence of cell transcription could not previously be measured as accurately as in this study, the dogma was:

"Transcription factors are the on-off switch essential
to initiate transcription of individual genes.

This is not true for embryonic stem cells — and potentially not for other cell types either.
"Transcription factors are still a key signal, but they do not drive the process as previously thought.

Once transcription factors are there, the gene can be read. They remain in place for a while after the gene is read — then they are gone. The window in which the gene can be read closes.

You can compare it with the vapour trails you see in the sky after an airplane passes. They linger for a while but slowly dissipate."

William Hamilton PhD, Assistant Professor, Center for Stem Cell Research and Developmental Biology (DanStem), University of Copenhagen, Denmark.

This discovery is first and foremost basic knowledge, which changes fundamental assumptions in molecular biology.

Thse new results are especially important for researchers working on stem cells and in cancer biology.

They provide new insight into how cells develop, how pathways involved in development determine when cells change, and when the point of no return is reached.

As these pathways are also found frequently mutated in cancer, the findings in this study will be valuable to the study of malignant development.
"In the project, we focused on the fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signalling pathway, which is a signalling pathway from a receptor on the surface of a cell to DNA inside the cell nucleus. This pathway is dysregulated in many types of cancer.

We therefore hope much of the data in this study will help inform aspects of cancer biology by indicating new and specific ways to target this signalling pathway in cancer cells."

Josh Brickman PhD.

Central to understanding cellular behaviour in multi-cellular organisms is the question of how a cell exits one transcriptional state to adopt and eventually become committed to another. Fibroblast growth factor-extracellular signal-regulated kinase (FGF -ERK) signalling drives differentiation of mouse embryonic stem cells (ES cells) and pre-implantation embryos towards primitive endoderm, and inhibiting ERK supports ES cell self-renewal1. Paracrine FGF–ERK signalling induces heterogeneity, whereby cells reversibly progress from pluripotency towards primitive endoderm while retaining their capacity to re-enter self-renewal2. Here we find that ERK reversibly regulates transcription in ES cells by directly affecting enhancer activity without requiring a change in transcription factor binding. ERK triggers the reversible association and disassociation of RNA polymerase II and associated co-factors from genes and enhancers with the mediator component MED24 having an essential role in ERK-dependent transcriptional regulation. Though the binding of mediator components responds directly to signalling, the persistent binding of pluripotency factors to both induced and repressed genes marks them for activation and/or reactivation in response to fluctuations in ERK activity. Among the repressed genes are several core components of the pluripotency network that act to drive their own expression and maintain the ES cell state; if their binding is lost, the ability to reactivate transcription is compromised. Thus, as long as transcription factor occupancy is maintained, so is plasticity, enabling cells to distinguish between transient and sustained signals. If ERK signalling persists, pluripotency transcription factor levels are reduced by protein turnover and irreversible gene silencing and commitment can occur.

William B. Hamilton, Yaron Mosesson, Rita S. Monteiro, Kristina B. Emdal, Teresa E. Knudsen, Chiara Francavilla, Naama Barkai, Jesper V. Olsen and Joshua M. Brickman.

The authors thank M. Thomson for the NANOG–eGFP ES cells, T. Kunath for Erk2-KO cells, N. Festuccia for Esrrb-KO cells, H.H. Ng for the KLF2 and TFCP2L1 antibodies, the Brickman laboratory members for critical discussions, Y. Spector for sequencing assistance, H. Neil, M. Michaut and the DanStem Genomics Platform for technical expertise, support, and the use of instruments, S. Pozzi, N. Festuccia and P. Navarro Gil for advice on ChIP protocols, K. Stewart-Morgan for help with ATAC-seq, A. Azad and J. A. R. Herrera for bioinformatics advice and P. van Dieken for technical support and proof reading. This work was funded by grants from the Novo Nordisk Foundation, Danish Council for Independent Research (8020-00100B), Danish National Research Foundation (DNRF116) and Human Frontiers in Science (RGP0008/2012). The Novo Nordisk Foundation Centers for Stem Cell Biology and Protein Research are supported by a Novo Nordisk Foundation grant numbers NNF17CC0027852 and NNF14CC0001. R.S.M. is supported by a fellowship from the Lundbeck Foundation (R303-2018-2939).

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Nov 15 2019   Fetal Timeline   Maternal Timeline   News  

Embryonic stem cells beginning to differentiate into unique cell tissues.
CREDIT University of Copenhagen.

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