Instant Notes - Key concepts

Site:	Cell Molecular Biology
Course:	Developmental Neurobiology 2018-2019
Book:	Instant Notes - Key concepts

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Date:	Saturday, 18 May 2024, 5:01 PM

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1. Development

1. Development

Development is a gradual multi-step -highly regulated- process by which a complex multicellular organism arises from a single cell (the zygote).

Major processes involved in animal development are:

cell division -> increase in number of cells
cell migration -> change in spatial location of cells
cell differentiation -> diversification into specific cell types
pattern formation -> tissues and organs develop in the correct place and orientation within the embryo. Cells acquire different identities based on their spatial location. Cell identity is initially partly defined within broad territories of competence, and becomes progressively refined as tissues and organs are formed.
morphogenesis -> generation of the complex shapes and structures that characterize the adult body organization.

For a general overview on the stages of animal development refer to the online version of the book "Developmental biology, 6th edition - Chapter 2 - The Circle of Life: The Stages of Animal Development".

1.1. Differentiation

Cell differentiation is the process by which progenitor cells from an undifferentiated state (stem/progenitors) become structurally and functionally specialized in distinct cell types (e.g in the nervous system: different types of neurons and glial cells).

The structural and functional specificity of a cell depends on the proteins it synthesizes. With rare exceptions, all cells of a given organism contain the same genetic information (genomic equivalence).

Cell differentiation implies a specific pattern of gene expression in which a particular set of genes are turned on (expressed) or turned off (repressed) resulting in the establishment of specific cellular morphologies and functions.

Cell differentiation usually occurs in response to external signals (according to the environment in which the cell develops) and is guided and maintained through the crosstalk between transcription factors and epigenetic mechanisms.

1.2. Fate and Commitment

As development proceeds trough cell proliferation, migration and differentiation, the number of different cell types in the embryo increases. Progenitor cells are progressively committed towards specific cell types.

Cell fate describes the range of cell types a progenitor cell can give rise to during normal development.

Cell potency describes the repertoire of cell types a progenitor cell can give rise to in all possible environments (e.g. a cell can differentiate in a different type compared to its "normal fate" if it is experimentally grafted in an ectopic region of the embryo). In animal development, cell potency is progressively restricted (from totipotent to unipotent) until a cell becomes terminally differentiated.

As cell potency becomes restricted following each decision in the developmental hierarchy, cells are said to be committed to a certain fate and eventually differentiate in a specific cell type.

Although commitment is a continuous process, developmental biologists identify different stages in cell commitment as shown in the figure below.

A cell is said to be uncommitted if it has not yet received instruction directing it along a particular developmental pathway.

A cell is considered to be specified when it is directed to follow a certain developmental pathway and does so when it is in its natural environment or it is placed in a neutral environment. At this stage, the cell transplanted to an ectopic place can be re-specified toward a different fate by the action of external cues present in the new environment (cell commitment at this stage is reversible).

A cell is considered to be determined if its fate is fixed and can no longer be changed, regardless of the external cues. Determination to follow a specific developmental pathway coincides with loss of competence to follow alternative pathways.

But, are specialized cells irreversibly committed to their differentiated fate? think about it and read about experiments by John B. Gurdon and Shinya Yamanaka

1.3. Mechanisms of Cell Commitment

In animal development two main mechanisms are used for cell commitment to initiate a series of events that eventually result in cell differentiation:

Inheritance of cytoplasmic determinants (intrinsic- lineage related)
External inductive signals (extrinsic - context related).

Cytoplasmic determinants

A cell can divide to produce 2 daughter cells committed to different fates, and this can be due to intrinsic information inherited from the mother cell during cell division. Indeed asymmetric distribution of cytoplasmic regulatory factors necessary for specification (e.g. mRNAs and proteins such as transcription factors) can influence the fate of the daughter cells.

Asymmetric distribution of cytoplasmic determinants results in asymmetric cell division, a condition that frequently occurs in early development in invertebrate embryos (e.g. Drosophila) when maternal gene products, localized to particular egg regions, are asymmetrically distributed to different blastomeres during cleavage.

Inductive signals

Induction is an extrinsic process that depends on the position of a cell in the embryo, i.e. information instructing the cell to follow a certain fate is received from the environment surrounding the cells. Induction implies cell-cell communication; it is a process whereby one cell or group of cells can influence the developmental fate of another, and is a common strategy to control differentiation and pattern formation in development. For instance, two identical cells can follow different fates if one is exposed to an external signal (often produced by a different cell) while the other is not.

What is the nature of the inductive signals?

The inductive signals are often proteins released from one cell type that can interact with receptors on the surface of responding cells or pass the cell membrane (e.g. Retinoic Acid, a derivative of Vitamin A - Retinol) and interact with intracellular receptors.

How do they act?

The binding of the inductive signal with receptors on the target cell membrane initiates a signal transduction cascade that influences the activity of transcription factors and/or other proteins eventually regulating target gene expression. Inductive signals that interact with intracellular receptors act as ligand-dependent transcription factors.

Response to an inductive signal can be stereotyped, or graded. In the case of a graded response (i.e. dependent on the inductive signal concentration), the inductive signal acts as a morphogen.

The response to specific inductive signals depends on the competence of the receiving cell (i.e. the ability to receive the signal and to react in an appropriate manner through the appropriate cell surface receptors, signal transduction apparatus, or downstream target transcription factors). The loss of competence is one mechanism by which a cell becomes "irreversibly" committed (i.e. determined) to a given developmental fate by loosing the ability to respond to other inductive signals that drive towards alternative fates.

Two types of induction can be distinguished:

Instructive induction: the responding cell has a choice of fates and is instructed by the Inducer to follow one specific developmental pathway that is alternative to the one followed in the absence of inductive signals or in presence of different concentration of the same signals or different signals.
Permissive induction occurs when the responding cell is already committed to a certain fate (contains all the potentials that are to be expressed), and requires a permissive environment to enable the developmental pathway to be expressed. When the signal reaches a threshold concentration the cells can make only one kind of response which is determined by their developmental history.

As development proceed there is a continuous of inductive processes ranging from strongly instructive to fully permissive.

1.4. Mosaic and Regulative development

Based on classical studies of experimental embryology, embryo development was broadly divided into two categories: Regulative (classically associated to Vertebrates) and Mosaic (classically associated to Invertebrates). It is now clear that the development of all embryos involves a combination of both mechanisms.

Mosaic development: if development was exclusively controlled by cytoplasmic determinants, the fate of every cell would depend uniquely on its lineage, while its position in the embryo would be totally irrelevant. Thus, in "mosaic embryo" (which is an abstraction) the fate of the cell is governed entirely by its intrinsic characteristics, i.e. cytoplasmic determinants it inherits at cell division. In this scenario, each cell undergoes autonomous specification. If the cells are removed from the embryo they should, in principle, develop according to their intrinsic instructions and differentiate into the appropriate part of the embryo even if the rest of the embryo is not there.

Regulative Development: if development was controlled exclusively by inductive signals, the fate of every cell would depend mostly on its position in the embryo. The fate of the cell is governed by its interactions with other cells. Each cell is said to undergo conditional specification. If the cells are removed from the embryo they should not fulfill their normal fate because they lack the necessary interactions.

(think about what would be the relationship between cell potency and cell fate in a condition of Mosaic development versus Regulative development)

Read about the classical experiments on mosaic and regulative development on the book chapter "The developmental mechanics of cell specification"

1.5. Pattern formation

All embryos of a given species have a similar structure or body plan.
How does it occur?
During development each cell must differentiate according to its position in the embryo, so that the "correct" cell types arise in the correct place. In other words, cells must know where they are in relation to other cells in the embryo.This is achieved in the developing embryo by giving each cells a positional value in relation to the main embryonic axes. Regional specification describes any mechanism that tells a cell where it is in relation to other cells in the embryo, so that it can behave in a manner appropriate for its position.

How cells become aware of their position? What is the nature of the positional information?
Several model systems indicate that cells may acquire positional values on the basis of their distance from a source of a morphogen. A morphogen is a secreted substance that can influence cell fate having different effects at different concentrations (.i.e. to be able to specify multiple cell fates at once!). The positional information along an axis can be generated for example by the synthesis of a morphogen at one end of the axis, and by its diffusion away from the source, setting up a gradient. Cells at different position along the axis would receive different concentrations of the morphogen and this would induce different patterns of gene expression at different concentration thresholds. Such concentration-dependent patterns of gene expression would represent the positional identity of the cell. Besides the concentration of the morphogen, another important parameter for tissue patterning is related to the duration of morphogen activity.

Among the main morphogens that play a critical role in cell–cell signals in both development and disease, we found members of the Wnt family, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA).
Morphogen gradients incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction.

!!! Do not confuse the term morphogen with morphogenesis!!!

1.6. Morphogenesis and homeotic genes

During development the establishment of an axis is often followed by the division of the axis into repetitive series of similar but independent developmental units.
Segments occurs in many species, from the obvious segmentation in the body of insects, to the rhombomeres and somites of vertebrate embryos. These segments can be considered as developmental compartments, in which the clonal expansion of a particular cell line is constrained.
How can a cell and its clonal descendants be confined to a specific compartment?
This may occur simply because there is a physical barrier to cell mixing, or compartments may be defined by patterns of gene expression in the absence of any obvious boundary.

Homeotic genes give cells their positional identity. Different combinations of homeotic genes are expressed in response to different morphogen concentrations. The homeotic genes encode transcription factors that regulate downstream effector genes controlling differentiation and morphogenesis. Homeotic mutations cause cells to be assigned incorrect positional identities, resulting in the development of regionally inappropriate structures.
To read more on homeotic genes and development you can refer to the book chapter "The Origins of Anterior-Posterior Polarity"