Role of skeletal muscle in the epigenetic shaping of organs, tissues and cell fate choices.

Since July 2000, the members of the “Mouse Models of Human Diseases Laboratory” have been able to study the role of muscle in the epigenetic shaping of developing tissues and organs employing an approach based on mouse mutagenesis and pathology. Muscle tissue is one of the four basic tissue types that the body consists of. There are three types of muscle tissue and we are interested in one of them, the skeletal or striated muscle. We can study the developmental role of muscle in the whole mouse embryo or fetus, because it is enough to knock out two myogenic regulatory factors (MRFs), Myf5 and MyoD, to obtain an embryo without any skeletal musculature. Obviously, such a fetus cannot survive after birth, but it is viable as long as it is in the womb.

Even though it is understandable that the muscle may have numerous functions during development, we think of muscle as either an executor of various movements or as a provider of neurotrophic factors. Therefore, I will concentrate on the description of two major research programs performed in this laboratory:

The first one, also known as developmental morphodynamics, deals with studies that examine the ability of muscle to provide mechanical cues for organogenesis. In this program, we are trying to understand mechanical control of tissue morphogenesis during development. In fact, the analysis of Myf5:MyoD compound nulls reveals that several organs have difficulties to fully develop in the absence of the musculature. Organs that depend on continuity between pre- and post-natal motility are: lung, retina, inner ear and some parts of the skeleton (e.g., mandible, clavicle, sternum and palate). Diseases or phenomena that are modeled in this research program include: pulmonary hypoplasia, motion vision, angular acceleration, cleft palate and sternum, temporomandibular and acromioclavicular joint agenesis.

The second research program is composed of experiments that test the neurotrophic hypothesis. In this program, we are trying to find out if there is a muscle-provided trigger of motor neuron death ultimately relevant to the motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The main reason for this kind of thinking is the fact that a complete absence of lower and upper motor neurons, which is the pathological definition of ALS, is achieved in the complete absence of the muscle.

Mutual embryonic inductive interactions between different tissue types and organs, between individual cell types belonging to the same or different lineages, and between various kinds of molecular players, are only some examples of the complex machinery that operates to connect genotype and phenotype. Our studies so far indicate that some aspects of this interplay can indeed be studied as proposed, confirming the role of skeletal muscle contractile and secretory activity in the epigenetic shaping of organs, tissues and cell fate choices. We will continue this analysis to gain more insight into the nature of the epigenetic events that lead into the emergent properties of a phenotype.