Lecture 4- Morphogens

A soluble secrete molecule that acts at a distance to specify the fates of cells. A morphogen may specify more than one type by forming a concentration gradient

• Source: cell initiates and maintains production of morphogen • Signal concentration gradient: morphogen diffuses away from the source down a concentration gradient • Sink: cells furthest from the source who receive the morphogen at the lowest concentration

• Cells fate is determined by a threshold * If the morphogen reaches the cell above a certain threshold, a certain fate is specified

• A gene mutated resulted in the loss of patterning * But not all molecules involved with patterning are morphogens

• As the amount of morphogen decreases, a new fate is specified • The closer you are to the source/the higher the morphogen concentration, the more rapidly the cell fates will change with movement away from the source • The further from the source/the lower the morphogen concentration, the cell fates will change less rapidly with movement away from the source • The information is more dense by the source where the gradient is steeper

• The diffusion away from the source results in all the same cell fate as they are all above the highest threshold • So will gain more cells where their fate is dependant on higher levels of morphogen • A similar pattern is then followed as under ‘normal’ morphogen levels

• Even at the highest level of reduced morphogen won’t be enough to specify certain cell fates • Cell fates specified at higher concentrations/thresholds will be lost • But there will be an increase in cells specified at low concentrations/thresholds

• Instead of decaying quickly, the morphogen diffuses further (e.g more stable protein) • The leads to a flatter concentration gradient • Less cell fates specified overall as the gradient can only specify certain cell fates within a smaller range

• Curved gradient * Morphogen gradient moves away from the source but increases again as it moves closer to the ectopic source

• No morphogen so only cells which are specified by lack of morphogen will be observed • No information so no pattern is developed

• Morphogen gradient does not change with a change in distance • Cells will all have the same fate as all exposed to the same concentration of morphogen • Information is the same so no cell fate pattern is observed

• Induce different outputs at different concentrations 2. Act directly at a distance

The high concentration of morphogen induces a different output to lower concentration

A signal permits cells to respond to another source of information perhaps from a previously inherited cell fate determinants

• Using an ectopic morphogen • Morphogen/instructive signal would result in mirror image of patterning • Permissive signal would have no affect and show normal patterning of signal

• Morphogen/instructive signal would result in cells at the same fate • Permissive signal would show no effect as the effect is pre-determined

Morphogen: can effect cells at a distance away from the source Bucket brigade: cells provide information,ation to the adjacent cell which causes the adjacent cell to makes its own signal and provide information to the neighbouring cell to change its fate Both theories suggest the first cell is responsible for patterning the field of cells. However, morphogen specific the fate of all cells, in the bucket brigade, each signal induces another

• Restrict the morphogen movement so signal can only be received by adjacent cells • Other cells would all assume the fate that would be observed if no morphogen was present • Bucket brigade would not be affect and cells could still provide information to adjacent cells

• Make cell that lacks receptor for the morphogen released by the signalling cell • The cell that lacks the receptor doesn’t specify to its normal fate as can’t ‘see’ the receptor • The gradient still forms and doesn’t impact other cells so they still specify as normal • Bucket brigade theory wouldn’t be affected by this

• Passive diffusion would only generate a shallow gradient and be inefficient

• Binding to a molecules in the ECM (e.g HSPGs) and high concentrations of receptor can generate a steep gradient called restricted diffusion • Rapid degradation of the signal in the extracellular space may also generate a steep gradient

• HSPGs are found in the ECM and bind to ligands * Regulate diffusion by sequestration or slowing and facilitating diffusion

• A pit forms in the cell membrane and engulfs the morphogen in a vesicle • Repeated cycles of endocytosis and re-secretion through the cells allows certain morphogens to travel through the cell in a tissue and restricts its movement

Antibody staining shows that Dpp is found in vesicles and mutations that block vesicle formation cause Dpp to act in a juxtracrine manner