Mouse Model, Ret-S697A for Enteric Nervous System Function and Development Investigation

Lead Inventor: Franklin Costantini, Ph.D. Enteric Nervous System (ENS) Development Study in Transgenic Mouse Models In biomedical research, transgenic mouse models are used to provide a test subject as a substitute for humans. These mouse models are made by altering a gene of interest in a mouse's genome to induce or repress genetic expression. Although valuable, these mouse models need to be extensively investigated to validate that the desired model genotype was produced and the desired phenotype is being expressed. Understanding development and cell lineage are key to combating genetic and developmental diseases. Thus there is a need for new model systems that allow the study of cell lineage. One such model would be for the investigation of the cellular development of the enteric nervous system (ENS). The ENS is derived from neural crest cells and is responsible for the control of the gastrointestinal system of vertebrates. However, the development of the ENS is not yet well understood. Ret Tyrosine Kinase Role in the Development of the ENS This technology is a line of transgenic mice that aids in exploring the role of the Ret tyrosine kinase in the development of the ENS in vivo. This transgenic mouse model expresses a targeted S697A mutation in the Ret tyrosine kinase. This mutation altered a putative protein kinase A (PKA) phosphorylation site. Homozygous S697A mice demonstrated defective migration capabilities of the enteric neural crest cells (ENCCs), leading to the lack of ENS development in the distal colon. In vitro organ culture demonstrated that these mutant ENCCs had an impaired stimulation to glial-cell-line-derived neurotrophic factor. This model offers a method of investigating ENS development in general and the role of Ret tyrosine kinase in particular. Applications: • The study of ENS development via mutant ENCCs and impaired chemoattractant responses. • The study of mutant Ret expression and effect in ENCC stimulation and signaling. Advantages: • Developed and validated mouse model for the role of Ret tyrosine kinase in ENS development, easing research time and costs. • Model is useful for the investigation of ENCC signaling and method of cellular migration in ENS development. Patent Status: Copyright/Material Licensing Status: Copyright, Available for Sponsored Research Support Publications: Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. N. Asai, T. Fukuda, Z. Wu, A. Enomoto, V. Pachnis, M. Takahashi, and F. Costantini. Development, vol. 133, p. 4507-4516. Express Licensing: https://www.flintbox.com/public/project/7709/