Genetics and morphology of the middle ear ossicles in the developing mouse embryo
Lead Research Organisation:
King's College London
Department Name: Craniofacial Dev Orthodon and Microbiol
Abstract
I am interested in researching how the middle ear ossicles develop. Defects in these ossicles, such as fusion, are fairly common and lead to hearing problems. These defects can be seen by using CT (computed tomography) scans, which allow assessment of the patient s suitability for corrective ear surgery.
The middle ear is composed of three ossicles that form a chain linking the ear drum with the inner ear. The three ossicles are connected by joints, which can be malformed or absent, resulting in fusion of the middle ear and hearing loss. In these patients it is unclear how the defects observed arose. This is due to a lack of information available with respect to formation of these joints during normal development.
This research attempts to correct this deficit in our knowledge by investigating the middle ear, first in normal and then in mutant mouse embryos. Development of the mouse middle ear has been shown to be similar to that of humans and therefore information obtained from using mouse models can be directly related to human patients.
I plan to concentrate mainly on the first two ossicles and joint region, as this is the region where defects most often occur.
We would first like to know:
sum How the joint forms
sum What genes are involved in joint formation
sum How is the position of the joint determined
sum How do each of the three ossicles develop their individual specification (ie their difference from each other) during normal embryonic development.
Having identifies how this region of the middle ear normally forms we will use this information to investigate cases where there is an abnormality. For this we will be analysing a mouse embryo that has a mutation in a gene called TCOF1. Patients with defects in this gene develop Treacher Collins syndrome (TCS) which is associated with a fused middle ear and hearing loss in almost 100% of cases.
This work should give a clear picture of how the middle ear defects seen in TCS occur during embryology. Ultimately, such information may help patients with TCS by allowing for a more informed decision when the option for surgery is discussed.
The middle ear is composed of three ossicles that form a chain linking the ear drum with the inner ear. The three ossicles are connected by joints, which can be malformed or absent, resulting in fusion of the middle ear and hearing loss. In these patients it is unclear how the defects observed arose. This is due to a lack of information available with respect to formation of these joints during normal development.
This research attempts to correct this deficit in our knowledge by investigating the middle ear, first in normal and then in mutant mouse embryos. Development of the mouse middle ear has been shown to be similar to that of humans and therefore information obtained from using mouse models can be directly related to human patients.
I plan to concentrate mainly on the first two ossicles and joint region, as this is the region where defects most often occur.
We would first like to know:
sum How the joint forms
sum What genes are involved in joint formation
sum How is the position of the joint determined
sum How do each of the three ossicles develop their individual specification (ie their difference from each other) during normal embryonic development.
Having identifies how this region of the middle ear normally forms we will use this information to investigate cases where there is an abnormality. For this we will be analysing a mouse embryo that has a mutation in a gene called TCOF1. Patients with defects in this gene develop Treacher Collins syndrome (TCS) which is associated with a fused middle ear and hearing loss in almost 100% of cases.
This work should give a clear picture of how the middle ear defects seen in TCS occur during embryology. Ultimately, such information may help patients with TCS by allowing for a more informed decision when the option for surgery is discussed.
Technical Summary
Congenital aural dysplasias occur in 1 in 3,300 to 10,000 births. In patients with major microtia, dysplasias of the malleus and incus occur at an incidence of 98%, with the joint region between these two ossicles frequently malformed or absent. We are interested in looking at how and when these ossicles, and the joint between them, form during normal and abnormal development using the mouse as a model organism.
The project will involve:
Characterisation of genes expressed in the ossicles and joint region.
Explant culture of the middle ear.
Overexpression of genes thought to control position and development of the joint.
Fate mapping of the middle ear.
Investigation of mutants with defects in the joint region.
By investigating the genes and processes involved in formation of the middle ear ossicles and incudomalleal joint we will obtain a better understanding of how defects arise in patients with congenital aural dysplasia.
The project will involve:
Characterisation of genes expressed in the ossicles and joint region.
Explant culture of the middle ear.
Overexpression of genes thought to control position and development of the joint.
Fate mapping of the middle ear.
Investigation of mutants with defects in the joint region.
By investigating the genes and processes involved in formation of the middle ear ossicles and incudomalleal joint we will obtain a better understanding of how defects arise in patients with congenital aural dysplasia.
