We are interested in the cell fate decisions that sculpt the formation of organs and tissues. There are multiple ways to study a developmental process.  One of the most informative ways is to identify genes which, when mutated, disrupt that process.  Forward genetics has its roots in classical genetics and utilizes randomly induced or naturally occurring mutants.  The advantage of forward genetics is that the focus is on the process/tissue/organ of interest. The researcher then starts with a phenotype of interest and works towards identifying the affected gene.


Why perform a mutagenesis screen in the mouse?  Mice are mammals, and thus are the closest genetic model system to humans.  Forward genetics approaches are unbiased and a proven means to identify human disease genes through the development of animal models.  Mice are also particularly useful if you want to look at a process/tissue/organ that only occurs in tetrapods (vertebrates descended from those that migrated from the oceans in the Devonian period to live on land) such as limb or lung development. 


We are currently working with a variety of mouse mutants with defects cell fate decisions:


The epidermal compartment of the skin is multifunctional; it maintains early embryonic integrity, gives rise to hair follicles and protects the animal from the environment. We study genes that regulate the switch between cell division and differentiation, which is crucial for epidermis formation and maintenance. Defining how these genes maintain that crucial balance is essential to understand how the skin is built during development and also how human diseases like skin cancer develop.


In the long bones of the body (ex. limbs), the chondrocytes that form the initial cartilage template must go through an orderly process of maturation to form bone.  We are studying genes that affect the timing of this maturation, which is essential for normal bone length.  Determining how these genes influence chondrocyte maturation is key to understanding how syndromes like dwarfism occur, but may also shed light on how limb lengths diverge in different animal lineages.


Multiple human syndromes including, Joubert, Bardet-Biedl, Oral-Facial-Digital type 1, and Meckel-Gruber have been linked to defects in a small cellular organelle called the cilium.  Cilia are found on almost all cells in vertebrate embryos and have recently emerged as key regulators of animal development and disease. We are working with several mouse mutants that affect cilia development in an effort to understand 1) how cilia are built, 2) how cilia affect cell fate decisions in particular tissues, and 3) how cilia defects lead to disease.

FORWARD GENETICS IN THE MOUSE

LEFT, general scheme for a forward genetics screen for recessive embryonic defects.  By using two different inbred strains, the phenotype can be mapped via linkage to unique polymorphisms in the original mutagenized strain.