Advances in Anatomy Embryology and Cell Biology最新文献

The ear serves two vital functions of hearing and maintaining balance. It achieves these roles within three major compartments: the outer, the middle, and the inner ear. Embryological development of the ear and its associated structures have been studied in some animal models. Yet, the role of skeletal muscle in ear development and its related structures is largely unknown. Research suggests the outer ear and parts of the inner ear may require skeletal muscle for normal embryogenesis. Here, we describe the role of skeletal muscle in the development of the ear and its associated structures. Moreover, we report the possible consequences of defect in the skeletal muscle of the ear and the clinical correlates of such consequences.

The skeletal musculature and the cartilage, bone and other connective tissues of the skeleton are intimately co-ordinated. The shape, size and structure of each bone in the body is sculpted through dynamic physical stimuli generated by muscle contraction, from early development, with onset of the first embryo movements, and through repair and remodelling in later life. The importance of muscle movement during development is shown by congenital abnormalities where infants that experience reduced movement in the uterus present a sequence of skeletal issues including temporary brittle bones and joint dysplasia. A variety of animal models, utilising different immobilisation scenarios, have demonstrated the precise timing and events that are dependent on mechanical stimulation from movement. This chapter lays out the evidence for skeletal system dependence on muscle movement, gleaned largely from mouse and chick immobilised embryos, showing the many aspects of skeletal development affected. Effects are seen in joint development, ossification, the size and shape of skeletal rudiments and tendons, including compromised mechanical function. The enormous plasticity of the skeletal system in response to muscle contraction is a key factor in building a responsive, functional system. Insights from this work have implications for our understanding of morphological evolution, particularly the challenging concept of emergence of new structures. It is also providing insight for the potential of physical therapy for infants suffering the effects of reduced uterine movement and is enhancing our understanding of the cellular and molecular mechanisms involved in skeletal tissue differentiation, with potential for informing regenerative therapies.

We summarize how skeletal muscle and lung developmental biology fields have been bridged to benefit from mouse genetic engineering technologies and to explore the role of fetal breathing-like movements (FBMs) in lung development, by using skeletal muscle-specific mutant mice. It has been known for a long time that FBMs are essential for the lung to develop properly. However, the cellular and molecular mechanisms transducing the mechanical forces of muscular activity into specific genetic programs that propel lung morphogenesis (development of the shape, form and size of the lung, its airways, and gas exchange surface) as well as its differentiation (acquisition of specialized cell structural and functional features from their progenitor cells) are only starting to be revealed. This chapter is a brief synopsis of the cumulative findings from that ongoing quest. An update on and the rationale for our recent International Mouse Phenotyping Consortium (IMPC) search is also provided.

The effects of ionizing radiation on centrosomes have been well documented and reviewed by Saladino et al. (2012) and are only briefly addressed here. These results showed that exposure of tumor cells to ionizing radiation causes centrosome overduplication and the formation of multipolar mitotic spindles, resulting in nuclear fragmentation and subsequent cell death (Sato et al. 2000). By using a variety of cell lines derived from different types of human solid tumors, it was shown that exposure to 10 Gy γ-radiation resulted in a substantial increase in cells containing an abnormally high number of aberrant centrosomes that formed multipolar spindles, resulting in imbalanced chromosome separation followed by mitotic cell death and formation of multi- or micronucleated cells.

The synchronized distribution of centrosomal and genetic materials to the dividing daughter cells is critically important and depends on precisely orchestrated processes on structural and molecular levels. Structural and functional relationships between the nucleus and centrosomes facilitate cellular communication and coordination of cell cycle control and progression which becomes especially important during the transition from interphase to mitosis when synchrony between centrosomes and nuclear events is critical.

Centrosome functions are vitally important for all aspects of reproduction with essential functions during meiosis, fertilization, cell division, centrosome remodeling during cellular polarization for tissue formation, and all stages of subsequent embryo development. Any defects in centrosome organization and dynamics can result in meiotic spindle formation errors, meiotic division errors, infertility, subfertility, arrested or failed development, and predisposition to various diseases including cancer. These aspects of reproduction will be addressed in more detail in the following sections.

As major accomplishments and breakthroughs in centrosome research had been achieved by Theodor Boveri in reproductive cells with the invertebrate sea urchin being an ideal model system for such studies on fertilization, cell division, and embryo development, these studies also gave rise to Boveri's brilliant concept regarding cancer cells. He discovered that eggs fertilized with two sperm resulted in tripolar mitosis and abnormal cell division, similar to cells observed in cancer tissue.

Cellular polarization involves significant remodeling and decentralization of the nucleus-associated centrosome to focal points at the apical and basolateral surfaces which is associated with major remodeling of the microtubule system in which individual microtubules become nucleated and organized from the polarizing cell surfaces, as studied in polarizing epithelial cells (reviewed in Müsch 2004; Muroyama and Lechler 2017). These changes are associated with cellular asymmetry in preparation for cellular differentiation of previously non-committed cells. During this process, the previously nucleus-associated centrosome becomes deconstructed into specific centrosomal components which are now referred to as "non-centrosomal." At the present time we still only have limited information about this process and to understanding the mechanisms underlying the centrosome decentralization process. Gaining detailed insights is further complicated by the fact that there is considerable diversity in the molecular mechanisms of centrosome and microtubule reorganization.

Among the multiple and intriguing roles of centrosomes in cellular functions is the ubiquitin-proteasome-mediated protein degradation. It has been shown that proteasomes are concentrated at the mammalian centrosome which led to further studies to view the centrosome as a proteolytic center (Wojcik et al. 1996; Wigley et al. 1999; reviewed in Badano et al. 2005). Proteasomal components that are concentrated around the centrosome include ubiquitin, the 20S and 19S subunits of the proteasome, as well as the E3 enzyme parkin. These proteasomal components colocalize with the centrosomal marker γ-tubulin and co-purify with γ-tubulin in the centrosomal fractions after sucrose-gradient ultracentrifugation (Wigley et al. 1999). The localization, accumulation, and concentration of proteasomal components around centrosomes appear to be microtubule independent which has been shown experimentally by inhibiting microtubule functions. When intracellular levels of misfolded proteins were experimentally increased by either proteasome inhibition with drugs such as lactacystin, or by overexpression of misfolded mutant proteins, the centrosome-associated proteasome network became expanded and proteolytic components were recruited from the cytosol without involvement of microtubules. These studies revealed a critical role of centrosomes in the organization and subcellular localization of proteasomes (Wigley et al. 1999; Fabunmi et al. 2000).