I would like to understand which mechanism triggers the first cell differentiation after n divisions.

I read previous articles on SE and Wikipedia articles on cellular differentiation and embryogenesis but still fail to understand what exactly makes it so that starting from a given division cells suddenly start to be different.

Wikipedia claims that

In the first hours after fertilization, this cell divides into identical cells. In humans, approximately four days after fertilization and after several cycles of cell division, these cells begin to specialize, forming a hollow sphere of cells, called a blastocyst

but do not explain why they begin to specialize.

I could imagine

  • that a cell has a "counter" on the number of divisions which triggers differentiation after a given amount of divisions
  • or a chemical substance (either cell-borne or external) forces a change in the division

but why some cells would become "cell A" and some others "cell B"?

I am fairly sure that the biochemical mechanisms which regulate the life of a grown up mechanism can explain cellular differentiation (through hormones for instance) -- I am however interested by this specific moment, this n-th division where identical cells become differentiated.

  • $\begingroup$ There are two different questions here. One is how "identical" cells become different types of cells. The other is why do the cells start differentiating when they do. $\endgroup$
    – Bitwise
    Jul 15, 2013 at 4:36
  • $\begingroup$ I am interested in the why more than the how $\endgroup$
    – WoJ
    Jul 15, 2013 at 10:02
  • $\begingroup$ The why and the how are somewhat inseparable. $\endgroup$
    – canadianer
    Nov 15, 2014 at 3:02

3 Answers 3


The first differentiation in human embryogenesis is from early blastomeres into trophoblast, which forms the outer layer of the blastocyst, and inner cell mass (ICM). It may be unsurprising then that cells on the inside of the 8-16 cell stage morula differentiate into ICM whereas those on the outside differentiate into trophoblast. However it is currently unclear whether this is a causal relationship (the inside-outside model) or whether blastocyst patterning is set-up earlier in cleavage (such as in the apicobasal polarity model) or if it is some combination of the two.

You were correct in imagining that tissue patterning is determined by chemical substances: a very broad class called morphogens. Cells don't necessarily count how many times they have divided but cell division can certainly affect morphogen concentration and localisation. I suppose in some sense you could describe this as a clock. I wouldn't though, especially because mammalian cleavage is asynchronous.

One line of studies showed that a transcription factor called Tead4 specifies trophoblast$^{ref}$. It was then shown that Tead4 can be regulated by cell-cell contact (mediated by Hippo signalling) $^{ref}$. They hypothesised that the magnitude of cell-cell contact could provide a mechanism by which Tead4 localisation could be controlled in presumptive trophoblast and ICM. This could explain why the cells have different fates because inner cells are completely surrounded (more cell junctions) whereas outer cells are largely exposed to the medium. Note that I only provided that as an example of a possible mechanism. It is not confirmed and, as with any model, the real picture is incredibly more complex and likely involves many factors.

I'm reluctant to go into too much detail on this because you're asking about a complex process that is still under active study and I'm unclear as to how much information you actually want. A book could be written on this subject alone, and many review papers have been published. Here's a recent one:

Development: Do Mouse Embryos Play Dice?

I suggest you read that and then if you have further, more specific questions, we can try and answer them for you.

  • $\begingroup$ Thank you for the detailed answer. It looks like a horrendously complicated mechanism (I have a PhD in Physics and the basic ideas can be explained with some hand waving - I was foolishly expecting the same in embryogenesis :)). $\endgroup$
    – WoJ
    Nov 16, 2014 at 11:59
  • $\begingroup$ I guess the hand wavy explanation would be that tissue patterning is done by chemical signals which can come from a variety of sources. In the case of the first differentiation in human development, the exact mechanism has yet to be fully characterised. It could be that the cells on the inside are in a different environment than the outside cells and so develop differently. Or it could be that the cells that become the inside are already fated for a certain development path. $\endgroup$
    – canadianer
    Nov 16, 2014 at 13:44
  • $\begingroup$ Also, I sometimes ask basic physics questions and even the hand waving explanations tend to go over my head. For me, hand waving only begs more questions. $\endgroup$
    – canadianer
    Nov 16, 2014 at 13:54

Why cells differentiate or specialize is an ephemeral question. I'll make an attempt to answer--the more specialized cells an organism has, the better equipped that organism is to function.

In a given organism, differentiation after n divisions or after t time during development is due to changes that are both intrinsic (genetic) or extrinsic (environmental). For two examples of how intrinsic and extrinsic determinants interact are:

"Unfolding a chordate developmental program, one cell at a time: invariant cell lineages, short-range inductions and evolutionary plasticity in ascidians."


"Cell Patterning"

If a cell changes after n divisions at t time, it may be due to its local cellular environment, or in the case of some animals, hormonal regulation that each cell may respond to differently.

As such, why do cell differentiate? Because in organisms, which are large collections of cells, survival is wholly dependent on the segregation of cellular function.

  • 1
    $\begingroup$ It would be great if you used some references to support your response! $\endgroup$ Oct 15, 2014 at 23:06
  • $\begingroup$ Thanks! I've done that and edited my response accordingly. $\endgroup$
    – rAntonioH
    Oct 15, 2014 at 23:50
  • $\begingroup$ Thank you for the answer and the links but I was not really asking why cells differentiate in general but rather what mechanism triggers the first cell differentiation. Possibly in an understandable way (which, per my comment above, seems to be rather difficult) $\endgroup$
    – WoJ
    Nov 16, 2014 at 12:02

Richard and Natalie Gordon proposed that there is a mechanically sensitive bistable organelle in the apical ends of cells in cell sheets about to differentiate (competent) and they are under mechanical tension. Depending on where the cell is on the sheet the tension will be resolved by either the apical end contracting or the apical end expanding. This will result in a biomechanical transduction signal from the cytoskeleton that is passed on to the nucleus which then changes gene expression. If the cell has experienced contraction, one signal is sent and it the cell has experienced expansion then another signal is sent. The signal is the determination of cell fate and is done by the cytoskeleton. They have outlined their research and their theory of differentiation waves in detail in their book "Embryogenesis Explained". In your specific example, the first differentiation takes place during mammalian compaction. Cells on the outside expand and become determined to be trophoblast, cells on the inside contract and become determined to be the inner cell mass. All the other stuff, gene expression changes, signalling proteins and the rest are secondary, the result of differentiation after the cytoskeleton determines cell fate with mechanical signals. Note this hypothesis is very detailed and specific, relatively simple overall, and based in mechanics and physics. It is highly testable with no "hand waving". You can read the short version of the theory for free in https://link.springer.com/article/10.1186/s12976-016-0037-2


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