S377 Chapter 17

Differentiation is the process by which cells become [blank_start]specialized[blank_end]; it involves a sequence of molecular events that result in differential [blank_start]gene expression[blank_end], which, in turn, determines the [blank_start]proteins[blank_end] that a cell will express.

Differentiation takes place both during development and in mature tissues.

Animal development involves a series of overlapping processes. [blank_start]Cleavage[blank_end] divisions, which form the [blank_start]blastula[blank_end], are followed by [blank_start]gastrulation[blank_end], during which the three germ layers (ec[blank_start]toderm[blank_end], m[blank_start]esoderm[blank_end] and en[blank_start]doderm[blank_end]) are formed and specification of the n[blank_start]eurectoderm[blank_end] and the anterior–posterior axis take place. The neural tube forms during [blank_start]neurulation[blank_end], and body segmentation begins. Finally [blank_start]organogenesis[blank_end] and in some species, metamorphosis, occur.

[blank_start]Differentiation[blank_end] involves molecules that are evolutionarily conserved between animal species, and act in different places and at different times during [blank_start]animal development[blank_end]. These molecules include [blank_start]transcription factors[blank_end], and a number of different secreted and cell surface [blank_start]signalling proteins[blank_end], their receptors and downstream intercellular signalling molecules. Differential exposure to signalling molecules results in [blank_start]differential activation[blank_end] of transcription factors, leading to [blank_start]differential gene expression[blank_end].

Differentiation is studied by cell a[blank_start]blation[blank_end], cell t[blank_start]racing[blank_end], transplantation, genetic analysis and cell culture techniques.

Similar mechanisms are involved in differentiation of different cells and tissues, of all animal species studied. These mechanisms include [blank_start]asymmetric division[blank_end], cell interactions, protein and mRNA [blank_start]gradients[blank_end] and [blank_start]combinatorial[blank_end] control.

Induction and patterning of the mesoderm, like that of other embryonic tissues, involves protein and mRNA gradients and combinatorial control.

Development of the cells of the nervous system involves a series of events, including neural [blank_start]induction[blank_end], [blank_start]neurulation[blank_end], patterning of the [blank_start]central nervous system[blank_end], neuronal [blank_start]differentiation[blank_end], migration of [blank_start]neural crest cells[blank_end] and [blank_start]axon guidance[blank_end].

In amphibians, neural induction involves inhibition of the action of BMP and Wnt proteins, by proteins that include [blank_start]Noggin[blank_end] and Frzb secreted by cells of the [blank_start]organizer[blank_end].

Inhibition of [blank_start]BMP signalling[blank_end] in the presumptive [blank_start]neurectodermal[blank_end] cells results in [blank_start]downregulation[blank_end] of the transcription factor GATA-1 which drives [blank_start]epidermal[blank_end] differentiation, and activation of [blank_start]neural transcription factors[blank_end], including neurogenin and NeuroD.

Increased expression of the cell surface signalling protein [blank_start]Delta[blank_end] results in increased activation of its receptor, [blank_start]Notch[blank_end], and also of [blank_start]neurogenin[blank_end] in adjacent cells. This upregulation results in [blank_start]reduced[blank_end] reciprocal signalling from the adjacent cell, which stimulates [blank_start]increased[blank_end] expression of neurogenin in the first cell, which in turn promotes expression of the transcription factor [blank_start]NeuroD[blank_end], and subsequent [blank_start]neuronal differentiation[blank_end].

A dorso-ventral gradient in [blank_start]Hox gene[blank_end] expression along the developing nervous system provides positional information, which results in the formation of different [blank_start]regions[blank_end] along the anterior–posterior axis of the brain and [blank_start]spinal cord[blank_end].

Different types of [blank_start]neuron[blank_end] are specified by expression of different [blank_start]regulatory genes[blank_end], induced by exposure to different levels of [blank_start]signalling molecules[blank_end], such as [blank_start]Shh[blank_end] and BMPs.

[blank_start]Neural crest[blank_end] cells give rise to a variety of cell types, including [blank_start]peripheral neurons[blank_end] and melanocytes. They arise from the neural tube, and undergo a transition from an [blank_start]epithelial[blank_end] to a mesenchymal state, which involves a change in expression of [blank_start]cadherins[blank_end] and other adhesion molecules. Neural crest cells [blank_start]migrate[blank_end] though the developing embryo along routes that are determined by cell surface molecules, ephrins, and by components of the [blank_start]extracellular matrix[blank_end].

The projections of growing axons are determined by [blank_start]guidance cues[blank_end]; both diffusible and [blank_start]contact-mediated[blank_end] signalling are involved. Proteins in the environment of the growing axon are detected by [blank_start]receptors[blank_end] expressed on the [blank_start]growth cone[blank_end]. Axons of [blank_start]commissural[blank_end] neurons, which cross the developing spinal cord, are first attracted by [blank_start]netrins[blank_end], and then their onwards trajectory is determined by [blank_start]repulsive[blank_end] signals from the proteins [blank_start]Slit[blank_end] and semaphorin.

Differentiation occurs in some tissues throughout life. An example is that of [blank_start]intestinal[blank_end] epithelial cells, which form from a pool of [blank_start]stem cells[blank_end] in the intestinal [blank_start]crypts[blank_end].

Adult [blank_start]stem cells[blank_end] exist in many [blank_start]differentiated[blank_end] tissues. Evidence suggests that their [blank_start]potential[blank_end] in vivo and in vitro may be broader than previously thought.

[blank_start]Embryonic[blank_end] stem cells are derived from the inner cell mass of mammalian [blank_start]early embryos[blank_end]. They can be engineered in culture to produce specific cell types. They are [blank_start]totipotent[blank_end], and can differentiate into any kind of cell, unlike most [blank_start]adult[blank_end] stem cells which are only [blank_start]multipotent[blank_end], where they can differentiate into several different types of cell, but not all.

Some cells may be able to [blank_start]de-differentiate[blank_end], after injury in vivo , or as a result of manipulation in vitro. And then [blank_start]trans-differentiate[blank_end] into another type of cell. An example is a newt regrowing a limb.

The [blank_start]transplantation[blank_end] of a nucleus from a fully or partially [blank_start]differentiated[blank_end] cell into an enucleated egg for the purpose of cloning requires [blank_start]reprogramming[blank_end] of the genetic material. (And it usually doesn't work!)