Cell fate determination

Within the field of developmental biology one goal is to understand how a particular cell (or embryo) develops into the final cell type (or organism), essentially how a cell’s fate is determined. Within an embryo, 4 processes play out at the cellular and tissue level to essentially create the final organism. These processes are cell proliferation, cell specialization, cell interaction and cell movement. Each cell in the embryo receives and gives cues to its neighboring cells and retains a cell memory of its own cell proliferation history. Almost all animals undergo a similar sequence of events during embryogenesis and have, at least at this developmental stage, the three germ layers and undergo gastrulation. While embryogenesis has been studied for more than a century, it was only recently (the past 15 years or so) that scientists discovered that a basic set of the same proteins and mRNAs are involved in all of embryogenesis. This is one of the reasons that model systems such as the fly (Drosophila melanogaster), the mouse (Muridae), and the leech (Helobdella), can all be used to study embryogenesis and developmental biology relevant other animals, including humans. What continues to be discovered and investigated is how the basic set of proteins (and mRNAs) are expressed differentially between cells types, temporally and spatially; and whether this is responsible for the vast diversity of organisms produced. This leads to one of the key questions of developmental biology, how is cell fate determined?

Cell Fate
In the past 15 years or so, the development of new molecular tools (see GFP) and major advances in optical microscopy (see microscopy) have made cell lineage tracing easier and more dynamic. This technique is used to study cells as they are differentiating into their final cell fates. Merely observing a cell as it becomes differentiated (see Cell differentiation) during embryogenesis provides no indication of the mechanisms that drive the specification. Therefore, the addition of molecular manipulation techniques, including gene and protein knock downs, knock outs and overexpression, along with live cell imaging techniques has been transformational in understanding what mechanisms are involved with cell fate determination. Transplantation experiments are commonly used in conjunction with the genetic manipulation and lineage tracing. Transplantation experiments are the only way to determine what state the cell is in on its way to being differentiated.

For a number of cell cleavages (the specific number depends on the type of organism) all the cells of an embryo will be morphologically and developmentally equivalent. This means, each cell has the same development potential and all cells are essentially interchangeable, thus establishing an equivalence group. The developmental equivalence of these cells is usually established via transplantation and cell ablation experiments.

The determination of a cell to a particular fate can be broken down into two states where the cell can be specified (committed) or determined. In the state of being committed or specified, the cell type is not yet determined and any bias the cell has toward a certain fate can be reversed or transformed to another fate. If a cell is in a determined state, the cell’s fate cannot be reversed or transformed. In general, this means that a cell determined to differentiate into a brain cell cannot be transformed into a skin cell. Determination is followed by differentiation, the actual changes in biochemistry, structure, and function that result in specific cell types. Differentiation often involves a change in appearance as well as function.

Modes of Determination
There are three general ways a cell can become specified for a particular fate; they are autonomous specification, conditional specification and syncytial specification.

Autonomous Specification
This type of specification results from cell-intrinsic properties; it gives rise to mosaic development. The cell-intrinsic properties arise from a cleavage of a cell with asymmetric cytoplasmic determinants (proteins, small regulatory RNAs and mRNA). Thus, the fate of the cell depends on factors segregated into the cytoplasm during cleavage. Autonomous specification was demonstrated in 1887 by a French medical student, Laurent Chabry working on tunicate embryos . This asymmetric cell division usually occurs early in embryogenesis.

Positive feedback can create asymmetry from homogeneity. In cases where the external or stimuli that would cause asymmetry are very weak or disorganized, through positive feedback the system can spontaneously pattern itself. Once the feedback has begun, any small initial signaling is magnified and thus produces an effective patterning mechanism. This is normally what occurs in the case of lateral inhibition in which neighboring cells induce specification via inhibitory or inducing signals (see Notch signaling). This kind of positive feedback at the single cell level and tissue level is responsible for symmetry breaking, which is an all-or-none process whereas once the symmetry is broken, the cells involved become very different. Symmetry breaking leads to a bistable or multistable system where the cell or cells involved are determined for different cell fates. The determined cells continue on their particular fate even after the initial stimulatory/inhibitory signal is gone, giving the cells a memory of the signal.

Conditional Specification
In contrast to the autonomous specification, this type of specification is a cell-extrinsic process that relies on cues and interactions between cells or from concentration-gradients of morphogens. Inductive interactions between neighboring cells is the most common mode of tissue patterning. In this mechanism, one or two cells from a group cells with the same developmental potential are exposed to a signal (morphogen) from outside the group. Only the cells exposed to the signal are induced to follow a different developmental pathway, leaving the rest of the equivalence group unchanged. Another mechanism that determines the cell fate is regional determination (see Regional specification). As implied by the name, this specification occurs based on where within the embryo the cell is positioned, it is also known as positional value. This is based on the observations that tissue taken from the thigh region of a chick embryo and grafted onto the wing does not transform to wing tissue, instead the tissue forms a toe.

Syncytial Specification
(See main article on Syncytium)

This type of a specification is a hybrid of the autonomous and conditional that occurs in insects. This method involves the action of morphogen gradients within the syncytium. As there are no cell boundaries in the syncytium, these morphogens can influence nuclei in a concentration-dependent manner.