Cell fate determination
Encyclopedia
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?
) 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.
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 .
s. 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 .
)
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.
, see Lau S et al., Cell-cell communication in Arabidopsis early embryogenesis. Eur J Cell Biol 2010, 89:225-230..
For a good review of the part of the history of morphogen signaling and development see Briscoe J, Making a grade: Sonic Hedgehog signalling and the control of neural cell fate. EMBO J 2009, 28:457-465.
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
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
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
and have, at least at this developmental stage, the three germ layers and undergo gastrulation
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
. 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
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
. This is one of the reasons that model systems such as the fly (Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
), the mouse (Muridae
Muridae
Muridae is the largest family of mammals. It contains over 600 species found naturally throughout Eurasia, Africa, and Australia. They have been introduced worldwide. The group includes true mice and rats, gerbils, and relatives....
), 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 GFPGreen fluorescent protein
The green fluorescent protein is a protein composed of 238 amino acid residues that exhibits bright green fluorescence when exposed to blue light. Although many other marine organisms have similar green fluorescent proteins, GFP traditionally refers to the protein first isolated from the...
) and major advances in optical microscopy (see microscopy
Microscopy
Microscopy is the technical field of using microscopes to view samples and objects that cannot be seen with the unaided eye...
) 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
Equivalence group
An equivalence group is a biology term used to describe a set of unspecified cells that have the same developmental potential or ability to adopt various fates. Our current understanding suggests that equivalence groups are limited to cells of the same ancestry, also known as sibling cells...
. 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 cleavageCleavage
Cleavage may refer to:*Cleavage , partial exposure of the separation between a woman's breasts.**Cleavage enhancement, methods of making a person's breast cleavage look more substantial than it really is....
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
Lateral inhibition
In neurobiology, lateral inhibition is the capacity of an excited neuron to reduce the activity of its neighbors. Lateral inhibition sharpens the spatial profile of excitation in response to a localized stimulus.-Sensory inhibition:...
in which neighboring cells induce specification via inhibitory or inducing signals (see Notch signaling
Notch signaling
The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...
). This kind of positive feedback at the single cell level and tissue level is responsible for symmetry breaking
Symmetry breaking
Symmetry breaking in physics describes a phenomenon where small fluctuations acting on a system which is crossing a critical point decide the system's fate, by determining which branch of a bifurcation is taken. To an outside observer unaware of the fluctuations , the choice will appear arbitrary...
, 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 morphogenMorphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
s. 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
Morphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
) 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
Equivalence group
An equivalence group is a biology term used to describe a set of unspecified cells that have the same developmental potential or ability to adopt various fates. Our current understanding suggests that equivalence groups are limited to cells of the same ancestry, also known as sibling cells...
unchanged.
Another mechanism that determines the cell fate is regional determination (see Regional specification
Regional specification
In the field of developmental biology, regional specification is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.-Cell fate determination:...
). 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 SyncytiumSyncytium
In biology, a syncytium is a large cell-like structure; filled with cytoplasm and containing many nuclei. Most cells in eukaryotic organisms have a single nucleus; syncytia are specialized forms used by various organisms.The term may also refer to cells that are connected by specialized membrane...
)
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
Syncytium
In biology, a syncytium is a large cell-like structure; filled with cytoplasm and containing many nuclei. Most cells in eukaryotic organisms have a single nucleus; syncytia are specialized forms used by various organisms.The term may also refer to cells that are connected by specialized membrane...
. As there are no cell boundaries in the syncytium, these morphogens can influence nuclei in a concentration-dependent manner.
See also
Plant embryogenesisPlant embryogenesis
Plant embryogenesis is the process that produces a plant embryo from a fertilised ovule by asymmetric cell division and the differentiation of undifferentiated cells into tissues and organs. It occurs during seed development, when the single-celled zygote undergoes a programmed pattern of cell...
, see Lau S et al., Cell-cell communication in Arabidopsis early embryogenesis. Eur J Cell Biol 2010, 89:225-230..
For a good review of the part of the history of morphogen signaling and development see Briscoe J, Making a grade: Sonic Hedgehog signalling and the control of neural cell fate. EMBO J 2009, 28:457-465.