Molecular Machines and Tissue Architecture

The Laboratory of Molecular Machines and Tissue Architecture, led by Dr. Nasser M. Rusan, studies the role of centrosomes during animal development.

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Research Interests

Research Interests

Our lab studies centrosomes, non-membrane bound organelles that serve as the cell’s main microtubule (MT) organizing center (MTOC). Our efforts are focused on an outstanding question in the field – how does the centrosome tune its MTOC activity to support different functions? We use a combination of genetics, molecular biology, CRISPR gene editing, super-resolution microscopy, and other cell biological approaches. Most importantly, we employ the model organism Drosophila in combination with a powerful method of generating new alleles to investigate tissue specific functions. This approach has uniquely positioned my lab to discover unappreciated roles for centrosome proteins and is guiding our current research aimed to explore the etiology of centrosome- and cilia-related human diseases such as microcephaly and infertility.

Building Centrosomes

The centrosome is a non-membrane bound organelle that serves as the main microtubule (MT) organizing center of most animal cells. Centrosomes function to initiate and maintain cell polarity, guide cell migration, direct intracellular cargos, and properly distribute other organelles. In mitosis, centrosomes are critical for accurate construction of the mitotic spindle to ensure faithful chromosome segregation to the two daughter cells. Thus, it is not a surprise that defects in centrosome function lead to a wide range of failures at the cellular level, which in turn, leads to tissue defects and many human diseases. The lab aims to determine how centrosomes are properly constructed from their individual parts and how centrosomes function in a wide range of cell types to avoid human diseases such as polycystic kidney disease, microcephaly, cancer and many others.

centrosomes
  • A centrosome interactome provides insight into organelle assembly and reveals a non-duplication role for Plk4
    Galletta BJ, Fagerstrom CJ, Schoborg TA, McLamarrah TA, Ryniawec JM, Buster DW, Slep KC, Rogers GC, Rusan NM 
    Nature Communications, 7:12476

Bridge Proteins

For many years now, our lab has focuses on understanding how the centrosome ‘bridge protein’ Pericentrin-Like-Protein serves as both a negative and positive regulator of PCM assembly. We are specifically testing the hypothesis that PLP functions as a molecular switch to repel PCM in interphase and anchor PCM in mitosis. We aim to discover the upstream regulators of PLP and its downstream effectors.

  • Interphase centrosome organization by the PLP-Cnn scaffold is required for centrosome function
    Lerit DA, Jordan HA, Poulton JS, Fagerstrom CJ, Galletta BJ, Peifer M, Rusan NM
    Journal of Cell Biology, 210(1):79-97

Brain Development

An intimate link between centrosome function and neurogenesis is revealed by the identification of many genes with centrosome-associated functions mutated in microcephaly disorders. Consistent with the major role of the centrosome in mitosis, mutations in these centrosome-related microcephaly (CRM) genes are thought to affect neurogenesis by depleting the pool of neural progenitor cells, primarily through apoptosis as a consequence of mitotic failure, or premature differentiation as a consequence of cell cycle delay and randomization of spindle orientation. However, as suggested by the wide range of microcephaly phenotypes and the multifunctional nature of many CRM proteins, this picture of CRM gene function is incomplete. Our lab is investigating CRMs using Drosophila as a model system.

brain

CRMs and Asymmetric Division

Our lab has been interested in neural stem cell division regulation and brain development for 10 years now. We have focused on several genes critical for mitotic spindle development and centrosome function. Most prominently, we have studies the role of Abnormal Spindles (Asp) and the CRMs Pericentrin- Like-Protein (PLP).

  • Micro-computed tomography as a platform for exploring Drosophila development
    Schoborg TA, Smith SL, Smith LN, Morris HD, Rusan NM
    Development, 176685
  • An Asp-CaM complex is required for Centrosome-Pole Cohesion and Centrosome Inheritance in Neural Stem Cells
    Schoborg TA, Zajac AL, Fagerstrom CJ, Guillen RX, Rusan NM
    Journal of Cell Biology, 211(5):987-98

Male Fertility

Inheritance of genetic material from males in humans and many other animals requires flagellated motile sperm. The construction of sperm involves major, cell wide rearrangements of many complex cellular components including the nucleus, mitochondria, ER/golgi and the cytoskeleton. Failure in any of these rearrangements can result in sperm incapable of performing their function and subfertility in affected individuals.

sperm

Basal bodies in sperm and Head-Tail linkage

Our lab is interested in the proper formation of basal bodies (centriole) that ensures the nucleation and anchoring of cilia. In recent years, we have focused on sperm basal bodies and how they properly attach to haploid nuclei.

A major step in the assembly of a flagellated sperm is the establishment of a tight connection between the head, which contains the genetic material, and the tail, which provides the force for swimming. Failure to establish the connection can result in decapitated sperm and reduced fertility. At the center of this connection lies the centriole with one end anchored firmly at the nuclear envelope and the other end serving to root and template the microtubule based axoneme of the cilia/flagella that makes up the tail.

  • Sperm Head-Tail Linkage Requires Restriction of Pericentriolar Material to the Proximal Centriole End
    Galletta BJ*, Ortega JM, Smith SL, Fagerstrom CJ, Fear JM, Mahadevaraju S, Oliver B, Rusan NM* (* co-corresponding authors)
    Development Cell. 2020 53(1):86-101
  • Drosophila Pericentrin requires interaction with Calmodulin for its function at centrosomes and neuronal basal bodies, but not at sperm basal bodies
    Galletta BJ#, Guillen RX#, Fagerstrom CJ, Brownlee CW, Lerit DA, Megraw TL, Rogers GC, Rusan NM.
    (# co-first authors)
    Molecular Biology of the Cell, 2014 Sep 15;25(18):2682-94

Meet the Team

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Nasser Rusan, Ph.D.

Earl Stadtman Investigator

Nasser Rusan moved to the U.S. from Jordan in 1996. He graduated from the University of Massachusetts with a B.S. in molecular biology in 2000 and a Ph.D. in molecular and cellular biology in 2005. He conducted postdoctoral research at the University of North Carolina Chapel Hill from 2005-2011. He was awarded an American Cancer Society Postdoctoral fellowship in 2006, and received the University of North Carolina Postdoctoral Award for Research Excellence in 2009. Dr. Rusan joined the NHLBI in 2011 as an Earl Stadtman tenure-track Investigator. He is a member of the American Society for Cell Biology and serves on the editorial boards of Frontiers in Developmental and Cell Biology and Molecular Biology of the Cell (MBoC).

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