Lehigh University

Cohesinopathies and Ciliopathies - What's the Connection? - Summary Cilia Are Surface-exposed Organelles Found on Most Eukaryotic Cells, Needed to Sense and Transduce Varied Sensory Stimuli. Not Surprisingly, Mutations in Genes That Disrupt Cilia Growth or Function Result in 'ciliopathies' That Comprise a Wide Range of Developmental Syndromes and Multi-system Disorders. Cohesins Represent a Second and Independent Pathway That Is Critical for Development. Cohesins Are Required Inside the Nucleus for High-fidelity Chromosome Segregation, Gene Transcription, and Chromatin Organization. Mutations in Genes That Disrupt Cohesin Function Result in ‘cohesinopathies,’ Which Are Also Multi-syndrome and Multi-system Disorders. Both Ciliopathies and Cohesinopathies Are Characterized by Phenotypes Including Hearing Loss, Skeletal Abnormalities, and Cardiac Defects. Remarkably, Prior and Emerging Research Implicates Cohesins in Cilia Structure And/or Function. for Example, the Cohesin Protein SMC3 Localizes to Kinocilia in Hair Cells in the Zebrafish Embryonic Otic Vesicle (OV) (i.e. Kinocilia Are Specialized Cilia Specific to Hair Cells). Further, SMC3- Knockdown Leads to Otolith Defects in the Ov, and to Reduced Kinocilia Length in the Hair Cells of the Lateral Line (LL). These Knockdown Results Are the First Functional Evidence Connecting Cohesins With Cilia. Thus, the Long- Term Goal of This Research Is to Provide Mechanistic Insights Into How Cohesins and Cilia Functionally Interact. the Central Hypothesis Is That Overlapping Phenotypes in Cohesinopathies and Ciliopathies Are the Result of Unknown Shared Functions Between Cohesins and Cilia. the Overall Goal of This Proposal Is to Collect Preliminary Data Supporting the Model That Cohesin Proteins Contribute to Cilia Structure and Function. the Rationale for the Proposed Research Is That Revealing Such Connections Would Lay the Foundation for New Insights and Therapies That Will Impact Future Clinical Applications. the Hypothesis Will Be Tested Using Two Specific Aims: 1) Determine How Cohesin Contributes to Cilia Function, and 2) Determine How Cohesin Associates With Cilia. in the First Aim, Null Mutations in Cohesin Genes Will Be Generated. Mutants Will Be Monitored for Established Cilia Phenotypes and for Defects in Kinocilia Length. in the Second Aim, an MCHERRY-SMC3 Transgenic Line Will Be Generated to Monitor SMC3 Localization in Kinocilia. Additionally, Proximity Labeling Will Be Completed to Identify Putative Binding Partners in Cilia. This Approach Is Innovative Because This Research Has the Potential to Fundamentally Alter Our Understanding of Underlying Causes of Cohesinopathies and Ciliopathies, Which Would in Turn Influence the Future Development of Therapeutic Approaches. the Proposed Research Is Significant Because Connections Between Cohesins and Cilia Are Largely Unknown, Yet Are Fundamental to Our Understanding of Disease Phenotypes That Underly a Broad Group of Developmental Syndromes.