Trends in Cell Biology
ReviewDelta and epsilon tubulin in mammalian development
Section snippets
The neglected tubulins
The importance of tubulin family members α, β, and gamma (γ) is well recognized. α- and β-tubulin are the building blocks of all eukaryotic MTs and γ-tubulin is important in nucleating MT formation. Three additional superfamily members exist: δ, ε, and zeta (ζ) [1]; however, compared with their better-known relatives, little is known of their mechanism of action or function. A survey of the disparate but compelling data suggests this lack of focus is unwarranted and certainly not a reflection
Tubulin structure and phylogeny
α- and β-tubulin are compact proteins containing a nucleotide-binding domain comprising six alternating α-helices and β-sheets (H1–H6, S1–S6) at their N termini, an intermediate domain, and an acidic tail at their C-terminal domain. The C-terminal tail is the predominant site of post-translational modifications and MT-associated protein binding (Figure 1A) [9]. α-β-tubulin heterodimers polymerize with other heterodimers in a ‘head-to-tail’ manner forming protofilaments, which is driven via
Triplet MTs in mammalian centrioles
δ- and ε-tubulin genes have been found only in species that assemble centrioles comprising triplet MTs (Figure 2B). Although centrioles are most well known for their role in spindle formation, they are also the parent structure from which the basal body forms and ultimately the axoneme, which is the structural core of cilia/flagella (Figure 2C).
It should be noted that, while the evolutionary association between triplet MTs and δ- and ε-tubulin is strong and supported by a growing body of
δ-Tubulin
δ-tubulin was first localized to the centrosome in human bone osteosarcoma epithelial (U2OS) cells, in close proximity to γ-tubulin [16]. This localization was mirrored in mouse, rat, hamster, and frog cell lines; however, the specific cell types used to obtain these results are unclear [16]. By contrast, reports of δ-tubulin’s localization in mouse C2 myoblast cells suggest that it is localized to the centrosome during mitosis but is found across the cytoplasm and nucleus during interphase [4
δ-Tubulin
δ-Tubulin was first identified in the unicellular alga C. reinhardtii as a product of the UNI3 gene [27]. While this species typically possesses two flagella, uni3 mutants lacked one or both flagella. Ultrastructural examination revealed abnormal basal bodies that were missing C-tubules. The relationship between δ-tubulin and presence of the C-tubule was further supported by studies in C. reinhardtii, P. tetraurelia, and T. brucei [27., 28., 29., 30., 31.] (Table 2). Additional consequences of
Noncanonical tubulins in mammalian spermatogenesis
Mammalian male germ cell development is highly dependent on centriole and MT function. As is the case in somatic cells, centrioles function in spermatogonial mitosis and spermatocyte meiosis [48]. While both are expressed at high levels in murine germ cells, the role of δ- and ε-tubulin in germline centriole/centrosome function and in the other aspects of germ cell function remain untested [3]. Although molecular and structural differences are likely to exist between centrioles in somatic and
δ- or ε-tubulin in the early embryo
The transition from non-centrosomal to centrosomal MT organization that occurs in the preimplantation mouse embryo serves as a unique tool to test δ- and ε-tubulin’s involvement in de novo centriole formation. Mature murine oocytes are unequivocally acentriolar, meaning that the very early stages of embryonic development occur in the absence of active centrioles [60]. Centrosome-like structures are visible at the 64-cell stage in the outer (trophectoderm) cells of the mouse embryo [61] (Figure 4
Concluding remarks
While the importance of the tubulin superfamily is unequivocal, until the noncanonical tubulins δ and ε receive more attention, the tubulin superfamily’s full function and complexity will remain unappreciated (see Outstanding questions). δ- and ε-tubulin provide the MT cytoskeleton with an extra layer of structural complexity, which data increasingly suggest is essential for the acquisition of triplet MTs in many species. As highlighted throughout this review, the precise mechanisms by which δ-
Acknowledgments
G.G.S. is supported by an Australian Government Research Training Program Scholarship. J.E.M.D. is supported by a National Health and Medical Research Council Ideas Grant to M.K.O’B. and J.E.M.D. (APP1180929) and the concepts outlined in the grant were developed in part through funding from the Australian Research Council to M.K.O’B. (DP180100533). J.Z. is supported by a Canadian Institute for Advanced Research (CIFAR) Azrieli Scholarship. The Australian Regenerative Medicine Institute is
Author contributions
Conceptualization: G.G.S., J.E.M.D., J.Z., and M.K.O’B. Writing – original draft: G.G.S. Writing – review and editing: G.G.S., J.E.M.D., J.Z., and M.K.O’B. Visualization: G.G.S. Supervision: J.E.M.D., J.Z., and M.K.O’B.
Declaration of interests
The authors declare no interests.
Glossary
- Axoneme
- the core structure of cilia, which projects from the basal body as doublet MTs.
- Basal body
- in quiescent cells, centrioles usually exist as basal bodies. Here, centrosomes migrate to the cell periphery and in response to a range of molecular signals, the mother centriole transforms its composition and docks to the plasma membrane to seed cilia formation.
- Centriole
- a barrel-shaped organelle comprising MTs. In most species, centrioles possess nine sets of triplet MTs organized in a
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