Abstract
Mitotic spindle orientation is a conserved, dynamic, and highly complex process that plays a key role in dictating the cleavage plane, fate, and positioning of cells within a tissue, therefore laying the blueprint for tissue structure and function. While the spindle-positioning pathway has been extensively studied in lower-model organisms, research over the past several years has highlighted its relevance to mammalian epithelial tissues. Although we continue to gain critical insights into the mechanisms underlying spindle positioning, many uncertainties persist. In this commentary, we will review the protein interactions that modulate spindle orientation and we will present important recent findings that underscore epithelial tissue-specific requirements and variations in this important pathway, as well as its potential relevance to cancer.
Highlights
Robust regulation of mitotic spindle positioning is required for the proper development and maintenance of many epithelial tissues among a diverse array of organisms
The proteins that dictate spindle orientation are relatively well conserved across phyla, recent findings suggest that the requirements and mechanism of this process can vary according to tissue type
An additional level of regulation at the spindle pole involves phosphorylation by the pole-enriched Polo-like kinase 1 (Plk1) that can promote cortical dynein-dynactin dissociation from NuMA-LGN30. It remains unclear whether this is due to NuMA or dynactin phosphorylation or both, since both are Plk[1] targets (Figure 1 and Figure 2). These findings raise two important questions: (1) How do these multiple kinases coordinate with one another to maintain an appropriate balance of cortical and spindle pole NuMA pools? (2) Why do NuMA cortical accumulation and stability rely on two entirely separable mechanisms in metaphase and anaphase? One possibility is that metaphase NuMA must engage with dynamic cortical partners to promote continuous fine-tuning of spindle positioning, while cortical NuMA tethering to membrane phospholipids in anaphase is essential for driving efficient chromosome segregation and cell division
Summary
Robust regulation of mitotic spindle positioning is required for the proper development and maintenance of many epithelial tissues among a diverse array of organisms. Recent work has demonstrated the importance of spindle orientation in multiple mammalian tissues, including brain, retina, and epidermal appendages[4,5,6,7] Whether this process is a universal requirement for epithelial morphogenesis remains unclear. The LGN- and MT-binding domains of NuMA overlap and promote mutually exclusive interactions, so it remains unclear how these proteins cooperate at the cell cortex to direct spindle positioning[12] (Figure 1). One possibility is that metaphase NuMA must engage with dynamic cortical partners to promote continuous fine-tuning of spindle positioning, while cortical NuMA tethering to membrane phospholipids in anaphase is essential for driving efficient chromosome segregation and cell division Future studies addressing these questions, as well how Figure 2. Important goals of future research will be to determine whether oncogenic activation can disrupt spindle orientation and to definitively test the role, if any, of spindle orientation defects in epithelial cancer initiation or progression
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