Cleft PalateDefects in Midline Facial Development
By James Bedard
University of the Fraser Valley, BC
The discovery of the hedgehog gene (hh) by Nobel Prize winning scientists Eric Wieschaus, Christine Nusslein-Volhard and Edward Lewis helped identify many genes that control the segmentation, i.e., the future head-tail body patterning in fruit fly embryos. When hh function is lost by mutation, knock-out, or RNA interference (RNAi), the resulting embryos have a series of altered gene expression patterns, and may look like they have tiny projections covering the entire surface, just like the appearance of a hedgehog; hence the name.
Hh has very important roles in body patterning in fruit flies, including midline and limb development. Once hedgehog was discovered in Drosophila, scientists looked for an equivalent in mammals, where three homologs were discovered; desert hedgehog (dhh), indian hedgehog (ihh), and sonic hedgehog (shh)– which was named after the popular video game character! As with hedgehog, sonic hedgehog plays a critical developmental role in the notochord (structure that helps form the spinal cord), neural tube, gut, and limbs. Disruptions of the sonic hedgehog signaling pathway result in various types of birth defects in vertebrates, including humans.
One of the more common birth defects that can result includes cleft palate, which is a defect that affects the upper roof of the mouth. It is a relatively common birth defect that affects approximately 1 in 1000 newborn babies. Other birth defects related to midline development can be seen throughout the body and can include the face (cleft lip), brain defects (holoprosencephaly), neural tube defects (anencephaly, spina bifida), abdominal wall and gastrointestinal defects.
Currently cleft palate in humans is repaired by surgery, typically between 6 and 12 months of age. Gene therapy is not an option for treatment at this time, but may be in the future. However, shh gene therapy may not always be the right approach since cleft palate is heterogeneous, that is related to mutations in other genes and genetic syndromes.
Hedgehog and Sonic Hedgehog signals act as morphogens, or chemical gradients, that can induce cells to become differentiated (become different types of cells) depending on the specific concentrations of SHH. This gradient depends upon the type of responding cell, concentration, and time of exposure. Morphogens are molecules that direct the development of tissue patterns. They act through concentration gradients, and influence the movement and organization of cell types. They are important because they organize the developmental process in multicellular organisms. In Drosophila, hh expression patterns the body segments, legs, wings, eyes, and parts of the fly brain.
Shh and hh evolved from an ancestor that later split into the lineages that are today’s mammals and insects. Shh is expressed exclusively in mammals.
Drosophila hedgehog and human sonic hedgehog proteins are highly conserved; they share 96% sequence identity. Conservation of sequence identity in DNA, RNA, or proteins is used to identify regions of similarity between two or more sequences. This could imply structural, functional or evolutionary relatedness between the sequences.
So the next time you are playing your Sonic the hedgehog video game, remember the important role this gene had in shaping your own body!
- Why do you think mutations in SHH may not be fatal and/or result in non-life-threatening developmental defects?
- Can you explain how a morphogen works in development?
- Cleft palate
- a birth defect that affects the roof of the mouth, it is an opening in the roof of the mouth which that can be on one or both sides, or may go the full length of the palate.
- refers (in biology) to the degree that a DNA, RNA or protein sequence is maintained with a different DNA, RNA or protein sequence.
- Gene expression
- the process by which the information contained in some genes are used to synthesis a protein.
- Genetic syndrome
- a disease or disorder that has a group of identifying symptoms, whose cause is genetic.
- not all the same or contains different components.
- a birth defect of the brain, in which the front part of the brain fails to normally divide into the right and left hemispheres
- a gene found in one organism whose DNA sequence is similar to that of another organism and is believed to have originated from an ancestral single gene or common ancestor.
- is a technique used by developmental biologists in which a gene is deliberately made non-functional through genetic engineering.
- an imaginary line drawn vertically from the middle of the face and body forming two equal halves.
- a protein or substance that is present in embryonic tissues that induces developmental processes via a concentration gradient.
- Neural tube defects
- is the failure of the spinal cord (spina bifida) or brain (anacephaly) to close during early development of the developing fetus.
- a cartilage-containing structure found in all embryonic animals whose function is to support the body. Some adult animals, i.e. the vertebrates, lose the notochord during development.
- RNA interference (RNAi)
- is a technique to silence RNA expression, hence protein production in a cell or organism.
- Sequence identity
- is used to identify regions (DNA, RNA, or protein) of similarity between two or more sequences. This could infer structural, functional or evolutionary relatedness between the sequences.