Each differentiated cell type only makes the proteins coded for by a few percent of the 50,000 total genes.
For each of the 250 differentiated cell types, only certain proteins are made.
Selective expression of genes is what causes differentiation.

"Gene expression" (usually) refers to whether a given protein is synthesized, or not.
This is controlled mostly (but not entirely) by de-inhibiting transcription (messenger RNA synthesis) for the few percent of genes that a given cell expresses.
For example, all the cells of your body contain the genes (DNA that codes for) hemoglobin, but messenger RNA for hemoglobin is made (transcribed) only in red blood cells.

Somehow, all these 250 kinds of cells have to be in the correct geometric arrangements, to form all the tissues and organs.

Gene expression gets controlled at least the following four different levels:

A) Differential gene transcription ("transcriptional control") is the most important cause of differentiation, but not the only one. Other levels of control include the following:

B) RNA processing. For example, sometimes a given gene is transcribed in many cells, but then only some of these cells convert the transcript RNA into messenger RNA (by removal of introns, addition of other sequences, and transport into the cytoplasm). This is sort of like writing lots of letters, but only mailing some of them. It seems wasteful, but embryos sometimes use this method for creating certain important differences.

C) Selective translation of messenger RNAs. = "Translational control"" This method is often used to allow a quick increase of synthesis of certain proteins, for example in fertilized eggs. Messenger RNAs are made and stored in egg cells, but then not used for protein synthesis until after fertilization. Another use is for quantitative changes in amounts of protein made; for example, milk production can be increased by causing messenger RNA for the milk proteins to last longer in the cytoplasm before being destroyed by enzymes.

D) Modification of proteins. This means biochemical changes in proteins after synthesis. This can include controlling whether a given protein will be secreted by cells, and can also include changing how long the protein will last before enzymes digest it.

A non-embryological example is that the structural protein collagen cannot be finished and secreted if there isn't enough vitamin C. Scurvy is the name of the disease that results.
The symptoms result from inability to replace collagen. Including the collagen fibers that connect teeth to bones, collagen fibers in the walls of blood vessels, and in the skin.

How transcription is controlled in multicellular eucaryotes

Whether a given gene is transcribed is controlled by proteins called transcription factors, that bind to the DNA specifically wherever it has certain base sequences, and stimulate binding of the RNA polymerase enzymes that catalyse making RNA copies of each gene.

Usually, these binding sites are hundreds or a thousand+ base pairs "upstream" of the part of the gene that codes for the actual protein. These binding sites are called promoters. Mutations in the promoter region can prevent normal expression of a gene.

When a "reporter gene" such as the gene for GFP or for beta-galactosidase is inserted into DNA downstream of a certain promoter, then those proteins will be made in whichever parts of the body are made of cells with genes stimulated by that promoter.

Unexpectedly, it has been discovered that parts of the DNA thousands of base pairs distant from a gene (and sometimes even downstream of a gene!) can also stimulate transcription!!
These regions are called enhancers. The theory is that bending of the DNA brings enhancers close to the promoters, and somehow stimulates attachment of enzymes.

Eucaryote DNA is tightly bound to special proteins called histones. This binding inhibits binding of enzymes to the DNA, and therefore inhibits gene expression = m-RNA synthesis.

We should visualize transcription factors as prying histones lose from DNA that has the right base sequence to bind to that particular transcription factor. Thus, each kind of transcription factor is like a key "unlocking" transcription of the genes for which it is specific.

If two different genes have promoters with the same base sequence then a given transcription factor would cause both proteins to be made!

Many different families of transcription factors have been discovered. These are named for the structure of the part of the protein that actually binds to the DNA (upstream of the genes to be "turned on" or "off").

When sequencing a given gene shows that it contains an amino acid sequence like one of these families of transcription factors, that means that protein is itself a transcription factor.

You should learn the following names of these families:

Homeodomain transcription factors (including Hox genes!)

Basic helix-loop-helix transcription factors.

Basic leucine zipper transcription factors.

Zinc finger transcription factors.

Many specific examples of each kind will be mentioned in the course (and the textbook!) during the whole semester.

Transcription factors are a very big deal; Especially the ones coded for by hox genes!

In many cases, this differentiation is stimulated by signals sent from one cell to adjacent cells. This is called embryonic induction. A good example is the induction of the lens by the eye cup.

If you surgically transplant an eye cup to some other location, then (sometimes!) the skin at the other location will differentiate into lens.

The discovery of induction earned the Nobel Prize for Hans Spemann
(His graduate student discovered that notochord & somites induce ectoderm to become neural ectoderm, and some other effects; she died soon after from an accidental fire)

Prof. Bob Goldstein earned his job here by discovering an important and unexpected example of induction in early embryos of "the worm" C. elegans.

Sensitivity to embryonic induction occurs only in certain cells, at certain stages of development; it is called competence.

Many cases of induction are reciprocal interactions between epithelial cells and mesenchymal cells. Tooth formation is a good example. ("Reciprocal" meaning that both change their differentiated state.)

The outer layer of teeth is called enamel; it is secreted by special cells of the stomodeal ectoderm called ameloblasts. Enamel is very hard but (therefore) brittle.

The inner layer of teeth is called dentine is made by special cells called odontoblasts, which develop from the neural crest.

Unless they touch each other, neither will differentiate.
(but their induction can occur through tiny holes in millipore filters)
(transfilter induction of teeth was proven by UNC Professor Bill Koch, in the 1960s) (Mary Tyler was his Ph.D. student)

Many special examples of embryonic induction are described in chapter six of the textbook, along with newly discovered signal proteins, such as

sonic hedgehog,
fibroblast growth factor,
wnt,
bone morphogenetic hormone,

But let's try not to drown in details

Notice how the names of many genes come from what abnormalities are produced by mutations in that gene.

Mutation of the hedgehog gene causes fly embryos to abort with a shape that looks somewhat like a hedgehog. Later, vertebrate genes were discovered with very similar base sequences, and these genes were named after the character in the Sega computer game!

"Decapentaplegic" is another unfunny joke.
(think; what does "quadriplegic "mean? Well, insects have many more segments<P> Previous editions of this and other textbooks described experiments in which chicken (mouth) stomodeal ectoderm apparently had been induced to form tooth enamel by mouse neural crest mesenchyme.
(WEBSITE 6.1 mentioned on page 149)

Birds lost teeth in evolution midway through the mesozoic!
Was this because the inductive signal stopped being sent by their neural crest cells?
(imagine if Paul Revere were still waiting to see the message from the Old North Church, "One if by land and two if by sea")

A possible mistake in this research would be for some mouse ameloblasts to have been transplanted along with odontoblasts. For some reason, the new editions of textbooks are not emphasizing this research.
It could be because they just aren't as interested anymore, or because they think a mistake was made.

For the purpose of this course, you should understand what the experiment was supposed to be, why the results were so interesting and surprising, and what they implied about the genetic reasons for the loss of teeth in birds. A possible analogous result would be the induction of leg formation in snake embryos! Maybe most of the genes are still there for forming the lost structures?!

b) Name 5 specific examples of differentiated cell types.

c) Explain why you might expect the same or similar base sequences to occur in the promoter regions of genes that happen to be expressed in the same differentiated cell types?

d) In principle, what sort of mutation should be able to cause a given gene to become expressed in the wrong differentiated cell type? (for example, to cause skin cells to make hemoglobin?)

e) Transcription factors are what kind of molecule? (they are proteins)

f) Transcription factors bind specifically to what?

g) Deletion of both copies of the gene for a certain transcription factor would be expected to have what sort of phenotypic effect?

h) Why would you expect that the number of different genes for transcription factors should be more than the number of differentiated cell types, in a given species?

i) What effect does histone binding have on transcription of RNA copies of DNA?

g) What effect do transcription factors have on histone binding?

h) Can you guess (or did you read) how DNAase enzymes will tend to cut DNA strands at locations where transcription factors are bound to the DNA?

i) What is the distinction between promoters and enhancers?

j) What are "reporter genes" used for, and what are two examples? [And why can the effects of some reporter genes, but not others, be seen in living animals?]

k) In addition to the selective transcription of certain regions of DNA, in what other three ways do animals sometimes regulate gene expression?

l) What method is good for producing quick increases (or other adjustments) in the amount of certain proteins being made?

m) What does it mean about the function of a protein if it contains a zinc finger or a leucine zipper?

n) What are some other kinds of transcription factors?

m) Embryonic cell differentiation is sometimes controlled how? (Hint: so that tissues form in the correct geometric locations relative to each other!)

n) For what discovery did Hans Spemann win the Nobel Prize? (Who really made the discovery?)

o) What experiment seemed to prove that birds still have the genes for making tooth enamel, and that their embryonic oral epithelia still retain the competence to be induced to express these genes.

p) What is meant by reciprocal induction, and what is an example?

q) Some specific examples of proteins that serve as inductive signals are what?

r) If a certain gene was necessary to form the heart, why would geneticists name it the heartless gene?

s) If transcription factor proteins weren't too large to pass through plasma membranes, then could they sometimes cause embryonic induction?

t) Mutations in which different sorts of genes could cause certain cells not to differentiate at the right place, or possibly to differentiate somewhere else? (example, the gene for the receptor for the induction signal)