The Role of the MyoD Family Genes during Mouse Development

Citation

Patapoutian, Ardem (1996) The Role of the MyoD Family Genes during Mouse Development. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/7p08-6588. https://resolver.caltech.edu/CaltechTHESIS:10042021-225839792

Abstract

Myogenesis is studied as an example of vertebrate cell type determination and differentiation mainly due to the cloning and characterization of genes, both regulators and downstream structural genes, specifically expressed in this lineage. The studies presented in this thesis describe the regulation and function of the MyoD family of myogenic regulatory factors (MRFs) in the developing mouse embryo.

There are four known MRFs (MyoD, Myf-5, myogenin, MRF4/herculin/myf6) in vertebrates; all are exclusively expressed in skeletal muscle and their progenitors, but each with a unique and dynamic pattern. The individual function of one of these, MRF4, was tested by gene disruption via homologous recombination. MRF4 is required for proper muscle formation in a specific domain of the axial lineage during embryogenesis. Later in development, the muscle phenotype is rescued apparently by cellular compensation, suggesting partial redundancy between MRF members. However, an unexpected rib pattern formation defect was observed that caused the death of MRF4 null mice at birth. An inductive signal from muscle precursors to rib progenitors is postulated to be the cause for this malformation.

A differentiated cell is usually considered to be a terminal phenotype. However, the MRFs, when force expressed, have the unique capacity to transform various differentiated cells into a myogenic phenotype. Such a switch in phenotype seems to occur during normal perinatal development of esophagus muscle, as these cells transdifferentiate from a functional smooth type to skeletal muscle by sequentially expressing the MRFs, and then skeletal muscle-specific structural genes. This is one of the few examples of transdifferentiation that occurs during normal development of vertebrates.

The potent capacity of the MRFs to convert cells to a myogenic phenotype requires tight regulation of MRF expression as well as modulation of their function. Transgenic mice containing certain regulatory sequences from the Myf-5 locus, the first MRF to be expressed in all muscle lineages studied, drives the expression of a marker gene specifically in the early head but not trunk muscle precursors. This implies distinct regulatory pathways of initiating muscle determination in the two lineages. Furthermore, the head lineage is unique since Myf-5 is expressed at least three days before any of the other MRFs or muscle-specific differentiation genes are detectable, and suggests that Myf-5 function is under negative control.

Thesis Files