Fusome

The fusome is a membranous structure found in the developing germ cell cysts of many insect orders.Telfer, W. H. 1975. Development and physiology of the oocyte-nurse cell syncytium. Advances in insect physiology 11:223-319. DOI: 10.1016/S0065-2806(08)60164-2Snapp, E. L., T. Iida, D. Frescas, J. Lippincott-Schwartz, and M. A. Lilly. (2004). The fusome mediates intercellular endoplasmic reticulum connectivity in Drosophila ovarian cysts. Mol Biol Cell 15: 4512-4521. doi/10.1091/mbc.E04 – 06 – 0475.Greenbaum, M. P., T. Iwarmori, G. M. Buchold, and M. M. Matzuk. (2011). Germ Cell Intercellular Bridges. Cold Spring Harb Perspect Biol 3:a005850 doi: 10.1101/cshperspect.a005850 Initial description of the fusome occurred in the 19th century and since then the fusome has been extensively studied in Drosophila melanogaster male and female germline development. This structure has roles in maintaining germline cysts, coordinating the number of mitotic divisions prior to meiosis, and oocyte determination by serving as a structure for intercellular communication.de Cuevas, M., J. K. Lee, A. C. Spradling. (1996) α-spectrin is required for germline cell division and differentiation in the Drosophila ovary. Development 122: 3959-3968.Lilly, M. A., M. de Cuevas, and A. C. Spradling. (2000). Cyclin A associates with the fusome during germline cyst formation in the Drosophila ovary. Developmental Biology 218: 53-63. doi:10.1006/dbio.1999.9570

Structure

In D. melanogaster, germline cysts form from four mitotic divisions with incomplete cytokinesis that originated from one germline stem cell.Spradling, A. C. (1993). Developmental genetics of oogenesis. In The Development of Drosophila, M. Bate and A. Martinez-Arias, eds. (Cold Spring Harbor, New York: Cold Spring Harbor Press), pp. 1–70. Fuller, M.T. (1993). Spermatogenesis. In The Development of Drosophila, M. Bate and A. Martinez-Arias, eds. (Cold Spring Harbor, New York: Cold Spring Harbor Press), pp. 71–147. Incomplete cytokinesis results in intercellular bridges connecting every cell in the cyst, called ring canals3. The four mitotic divisions result in cysts of 16 cells connected by 15 ring canals. The fusome is composed of membrane vesicles and originates from endoplasmic reticulum. Fusome material is inside ring canals and can range in size from 1 to 10 um, depending on the stage of development.

1.1 Fusome Development

The spectrosome is a round structure in germline stem cells that develops into the fusome in cyst cells.Lin, H. and Spradling, A. C. (1995). Fusome asymmetry and oocyte determination in Drosophila. Dev. Genet. 16: 6-12. Fusome divides asymmetrically into daughter cells in females by attaching to one spindle pole during meiosis, resulting in one cell receiving all fusome material.de Cuevas, M. and A. C. Spradling. (1998). Morphogenesis of the Drosophila fusome and its implicaitons for oocyte specification. Development 125: 2781-2789.Roth, S. and J. A. Lynch. (2009). Symmetry breaking during Drosophila oogenesis. Cold Spring Harb Perspect Biol 1:a001891 doi: 10.1101/cshperspect.a001891 Fusome is generated de novo in the ring canal connecting the two cells. The two fusome parts then fuse together to connect the cells. Asymmetric fusome partitioning and new formation followed by fusion occurs at each mitotic division. In spermatogenesis, the fusome partitioning is symmetric and the fusome is still present during the meiotic divisions.Hime, G. R., J. A. Brill, M. T. Fuller. (1996). Assembly of ring canals in the male germ line from structural components of the contractile ring. J. Cell Sci 109: 2779-2788

1.2 Fusome components

Many proteins and organelles associate with the fusome throughout germ cell development. Cytoskeleton components, such as alpha and beta spectrins, hu-li tai shao (hts), and ankyrin were the first proteins identified in the fusome.Lin, H., L. Yue, and A. C. Spradling. (1994). The Drosophila fusome, a germline-specific organelle, contains membrane skeletal proteins and functions in cyst formation. Development 120: 947-956. Centrosomes travel along the fusome and the fusome is involved in microtubule organization.Grieder, N., M. de Cuevas, and A. C. Spradling. (2000). The fusome organizes the microtubule network during oocyte differentiation in Drosophila. Development 127: 4253-4264. The interactions between the fusome and microtubules result in cyst polarity in oogenesis. Associations between the fusome and microtubules change throughout the cell cycle. Mitochondria associates with the fusome and travel through ring canals to the oocyte.Cox, R. T. and A. C. Spradling. (2003) A Balbiani body and the fusome mediate mitochondrial inheritance during Drosophila oogenesis. Development 130: 1579-1590 doi:10.1242/dev.00365 Microtubules travel through ring canals and form the tracks for transport of materials between cells.

Function

There are numerous functions of the fusome as a structure necessary for cell-cell communication in developing germ cell cysts. The fusome connects cells, allowing for transport of proteins and RNAs between cells and synchronous activities. Mutations in essential fusome components can result in infertility.

2.1 Role in cell cycle synchrony

Developing cells in germline cysts undergo mitotic divisions synchronously and in males all cells in a cyst also undergo meiosis synchronously. The fusome is a track where an event can happen and then feedback mechanisms quickly communicate to each cell to ensure a specific outcome occurs simultaneously in every cell. Cells in a cyst fail to divide synchronously if the fusome is disrupted.Deng, W. and H. Lin. (1997). Spectrosomes and fusomes anchor mitotic spindles during asymmetric germ cell divisions and facilitate the formation of a polarizes microtubules array for oocyte specification in Drosophila. Dev Biol 189: 79-94. The rosette formation of germline cyst cells allows cells to be in the closest configuration for communication.

Throughout the cell cycle, different cyclins associate with the fusome to induce synchronous cell divisions. Cyclin A and Cyclin E localize to the fusome in female germline cysts and are required for the correct number of mitotic divisions to occur.Ohlmeyer, J. T. and T. Schupbach. (2003). Encore facilitates SCF-Ubiquitin-proteosome-dependent proteolysis during Drosophila oogenesis. Development 130: 6339-6349. doi:10.1242/dev.00855 Abnormal cyclin levels result in too few or too many divisions. Cyclin E at the fusome is phosphorylated for degradation by the SCF complex and if not degraded, an extra division occurs. The fusome may be the degradation site for other cell cycle proteins. Myt1 kinase inhibits CycA/Cdk1 in males during G2.Varadarajan, R., J. Ayeni, Z. Jin, E. Homola, S. D. Campbell. (2016).Myt1 inhibition of Cyclin A/Cdk1 is essential for fusome integrity and premeiotic centriole engagement in Drosophila spermatocytes. MBoC 27: 2051-2063. doi.org/10.1091/mbc.E16-02-0104 Without Myt1 regulation, fusome and centrosome behavior is abnormal, resulting in cells with irregular spindles.

2.2 Differences in male vs female fusomes

In females, the fusome plays a role in cell fate and differentiation. Asymmetric fusome distribution and centriole orientation determines which cell in the developing female germline cyst becomes the oocyte. One of the two cells from the first division within the cyst becomes the oocyte and contains the most fusome material. The fusome degrades after the 16-cell cyst forms. In females, the connections are the channels through which nurse cells send proteins and RNAs to the oocyte along polarized microtubules.

In males, the fusome is necessary for ensuring quality control in individual cysts. DNA damage in one cell leads to all cells in a cyst dying by communication through the fusome, either by disseminating a death signal or additive DNA damage inducing apoptosis.Lu, K. L. and Y. M. Yamashita. (2017). Germ cell connectivity enhances cell death in response to DNA damage in the Drosophila testis. eLife 6:e27960. doi.org/10.7554/eLife.27960 This ensures mature sperm cells have intact genomes before fertilizing an egg. In addition, the fusome connections ensure haploid spermatids have proteins and RNA made by the other chromosome for “gamete equivalency”.Braun, R. E., R. R. Behringer, J. J. Peschon, R. L. Brinster, and R. D. Palmiter. (1989). Genetically haploid spermatids are phenotypically diploid. Nature 337: 373-376.

Similar structures in other animals Fusomes were previously thought to be specific to insect gametogenesis. Fusome-like structures have been identified in Xenopus laevis oogenesis by electron microscopy and immunostaining for fusome components such as spectrin and hts.Kloc, M., S. Bilinski, M. T. Dougherty, E. M. Brey, and L. D. Etkin. (2004). Formation, architecture and polarity of female germline cyst in Xenopus. Dev Biol 266: 43-61. doi:10.1016/j.ydbio.2003.10.002 Intercellular bridges also connect developing germ cells in mammals, contributing to cell cycle synchrony and gamete quality control by sharing substances between cells. Future studies are required to elucidate all of the functions that arise from cell-cell communication through intercellular bridges. In addition, a future area of research is to determine why some organisms lack fusomes. Do these organisms have another structure that carries out the role of the fusome or are these roles not necessary in germline cyst development of these other organisms?

Fusome

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