Roux Lab

Defects in a cellular structure termed the nuclear envelope are associated with a myriad of diverse diseases, collectively called nuclear envelopathies. Most of these disorders clinically manifest during the first two decades of life and include muscular dystrophy, cardiomyopathy, lipodystrophy, dystonia, neuropathy, skeletal defects, and progeria. The nuclear envelope is situated at a critical juncture in the cell, both intimately associated with the genome and responsible for connecting it to the rest of the cell. While it is clear that mutations in genes encoding protein constituents of the nuclear envelope underlie these diseases, the exact mechanisms remain largely unknown. In part, these nuclear envelopathies involve a nuclear envelope structure called the LINC-complex that is responsible for linking the nucleoskeleton to the cytoskeleton.

Our laboratory investigates the structure and function of the mammalian nuclear envelope in health and disease. We have identified and are functionally characterizing several novel members of the LINC-complex. These proteins are retained on the outer nuclear membrane where they appear to perform specific roles in specialized cell types. We are also investigating the mechanisms by which defects in a single constituent of the nuclear lamina, the intermediate filament scaffold inside the nucleus, lead to a wide variety of diseases called laminopathies. These studies are supported by the BioID method to screen for interacting and proximate proteins.

Current projects

Development and application of BioID: We developed BioID to overcome methodological challenges in our studies on the structure and function of the nuclear envelope in health and disease. First applied to a disease-associated nuclear lamin, we demonstrated that BioID is effective at identifying proximate and interacting proteins. Ongoing studies include the application of BioID to uncover the mechanisms of disease for the nuclear envelopathies, expansion of its application to a myriad of subcellular domains, and further optimization of the BioID system.

Characterization of novel LINC-complex constituents: We have discovered several novel members of a mammalian family of outer nuclear membrane (ONM) proteins that connect the nucleus to the cytoskeleton and/or retain specific proteins at the ONM. One of these proteins, which we have named Dalek6, appears to help connect chromosomes to molecular motors during meiotic prophase I. We are investigating the role of Dalek6 in regulating the movement of meiotic chromosomes during the process of homolog pairing and synapsis. Defects in these events may contribute to aneuploidy, a common cause of prematurely terminated pregnancies and birth defects such as Down syndrome.

Investigating the mechanisms of disease for the laminopathies: Using novel techniques, we are currently exploring how mutations in lamin A/C lead a wide variety of disorders. Our aim is to identify differential protein interactions between normal and mutant lamins. The results of these studies may uncover the fundamental mechanisms of laminopathies and reveal new treatment options.

 

Contact Information for Roux Lab:

Kyle J. Roux, PhD


Scientist, Sanford Children's Health Research Center
Sanford Research
Sanford Research Center, Room 2245
2301 E 60th Street N
Sioux Falls, SD 57104
Telephone: 605-312-6418
Fax: 605- 328-0401
Email: Kyle.Roux@sanfordhealth.org