Investigating the Basis of Defective Morphogenesis in Mouse Models of NF2
Abstract
Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by the growth of noncancerous tumors in the nervous system. People born with this condition have inherited one mutated copy of the NF2 gene in all their cells. If the second copy of the NF2 gene becomes mutated specifically in the nervous system, this induces the formation of non-cancerous tumors in NF2 disease. Besides its involvement in Neurofibromatosis, NF2 (also known as Merlin) has further been linked to cancerous tumors, especially mesotheliomas of the lung. It is therefore very important to better understand the function of NF2/Merlin in normal ("healthy") conditions because this is a necessary first step before its roles in neurofibromatosis and cancer can be understood. Research performed mostly in the context of cells grown in a petri dish has revealed connections between NF2/Merlin and pathways that control how a cell responds to external signals (such as hormones and growth factors). As such, it is important to study these connections in the context of a living organism. Here we are proposing to use a very sensitive system, the developing kidney, to study the role of NF2/Merlin and its connection with various cellular pathways. As a first step, we have removed NF2/Merlin specifically in the kidneys of mice. Mice born without NF2 had small kidneys that also lacked the typical complex structural organization found in this organ. These defects could be rescued by removing other genes that normally exacerbate the loss of NF2, indicating that we can compensate for the loss of NF2/Merlin by manipulating other components in the kidney. To identify which other cellular components or pathways we should investigate in relation to NF2 with our mouse kidney model, we have also begun using methods to identify proteins that associate with NF2/Merlin. In fact, NF2/Merlin is a large protein, which likely acts to recruit other proteins to particular locations in the cell, permitting them to perform their normal cellular functions. We postulate that some of these proteins are not recruited to NF2/Merlin properly in the disease. We will design experiments that will enable us to find proteins that specifically associate with NF2/Merlin when it is active or inactive, akin to the different ways the protein is found in disease patients. This will permit us to better focus on the pathways that are most likely relevant to the patient s health. The proteins identified in this manner will be further studied in our mouse kidney model, providing a much better view of the function of NF2/Merlin in health and disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510461
Entities
People
- Helen Mcneill
Organizations
- Lunenfeld-Tanenbaum Research Institute
- United States Army