Insights from Embryology to Inform on Disease

Background and Aim: In vertebrates, head and axial muscles arise fromdifferent mesodermal origins, and their development depends on distinctgene regulatory pathways. Tbx1, Islet1 and Pitx2 govern cranial-derivedmuscle fates whereas Pax3 and Pax7 are critical for somite-derivedmuscles. It is unclear how the distinct genetic hierarchies have led to thisregional specification. Observations in the clinic have identified a widevariety of myopathies that affect subsets of skeletal muscles resulting indebilitating diseases. It is unclear why some muscles are affected while others escape the disease.Methods: We have used an extensive array of genetically modifiedmice, including knockouts and transgenics with lineage derived reporterconstructs to mark, perturb, and follow the fate of specific musclepopulations in the mouse. Multi-color and imaging strategies includingmicroCT scanning of 3D generated structures provide whole mountimaging views of the developmental trajectories that muscle stem andprogenitor cells use to effect morphogenesis and subsequent musclepatterning.Results: We have investigated the patterning of the extraocular (EOM),esophagus and neck muscles and provide evidence for a surprisingdiversity even among muscles of the same cranial embryological origin.Using a combination of genetic lineage drivers in the mouse and a varietyof imaging approaches, we provided a link between key transcriptionfactors, cell fates, and patterning. The complementary analysis of othervertebrate organisms including chick, fish has shed new light on theevolutionary relationships and functions of the neck and the associatedpectoral girdle apparatus.Conclusion: The use of mouse genetic strategies and imaging approacheshave provided important insights into tissue genesis as well as anunderstanding of the developmental origin of some human congenitaldiseases such as DiGeorge syndrome where subsets of cranial musclesare affected.

کلیدواژه ها:

Skeletal muscle development ، Genetic modification ، Lineage tracing ، Whole mount imaging ، Muscle stem cells