How Centrioles Control Mammalian Development

/Abstract Centrioles, the core of centrosomes, have multiple fundamental roles including generating cilia, organizing the microtubule cytoskeleton, and facilitating mitosis. Inherited defects in centrioles can cause important human congenital diseases, including congenital heart defects and ciliopathies. Despite their importance to development and disease, the molecular and cell biological mechanisms through which centrioles participate in mammalian development remain poorly understood. We have been investigating how centrioles function in mouse embryonic development. Remarkably, disruption of different parts of the centriole affect different development events. For example, the distal centriole component CEP97 is critical for cardiac septation, but dispensable for many other centriole- and cilia-dependent events. In contrast, the proximal centriole component ALMS1 is critical for maintaining brain cilia, but dispensable for heart development. Interestingly, we found that removing centrioles altogether affects different cell types differently. For example, removing centrioles from the intestinal epithelium does not affect its development, but removing centrioles from the lung epithelium blocks lung branching. Thus, not only do different parts of the centriole have different functions in development, but different cell types use centrioles in different ways. Our proposal builds on this work by investigating how centrioles direct mammalian development, with a focus on heart, lung and inner ear development. Using tools like centrosome affinity capture mass spectrometry (CAPture-MS) and pan-Expansion Microscopy of tissue (pan-ExM-t) to mitigate barriers in studying centrioles, we examine how centriole defects lead to human disorders such as congenital heart disease and Alström syndrome. In Aim 1, we focus on how CEP97 promotes ciliogenesis in the second heart field, essential for cardiac septation. We investigate how CEP97 controls centriole length to enable ciliogenesis. In Aim 2, we explore how removing centrioles activates the mitotic surveillance pathway (MSP) to disrupt lung branching. We seek to understand how some lung progenitors apoptose in response to MSP activation while others do not. In Aim 3, we study how a proximal centriolar protein, ALMS1, supports ciliogenesis and transition zone assembly on the other end of the centriole. Thus, in addition to illuminating how centrioles function in development and disease, this project investigates how centrioles are constructed, how centrioles mature to generate cilia, how centrioles promote cell survival, and how cells ensure that they have neither too few nor too many centrioles. Project Number: 1R01HL181088-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jeremy Reiter | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $568,177 | Activity Code: R01 | Study Section: Development - 2 Study Section[DEV2] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18108801