Fellow’s research: New insights into mechanisms that promote proper establishment of cell polarity


22 Dec 2019

Fellow’s research: New insights into mechanisms that promote proper establishment of cell polarity

 

Dr. Sachin Kotak, Intermediate Fellow, IISc, Bangalore

In our recently published study, we provide a mechanism by which Aurora A Kinase, a member of the Aurora kinase family of proteins that have multiple functions in cell division, promotes singularity in cell polarisation—a function essential to drive cell fate determination during development.

Existence of multicellularity in metazoans relies on the division of labour between different cell types. For the origin of various cell types, an organism ensures that the determinants of cell fate are properly segregated during development and in morphogenesis, which is formation of tissues and organs. Part of this problem is solved by guaranteeing the proper establishment of cell polarity (i.e. organisation of the cellular components) in different cell types. Various cells utilize a myriad of different signals to get polarized; for instance, epithelial cell polarize because of the cues obtained from their neighbouring cells, and yeast cells polarize when they receive signals from each other.

In the context of this study, it was known that embryos of the nematode worm Caenorhabditis elegans, which is an important laboratory animal model, polarize after fertilization. A sperm-based cue is responsible for the polarization of the one-cell embryo. Additionally, paternally contributed centrosomes, but not the genetic material, were shown to be critical for the polarity set-up in these embryos. However, the nature of the centrosome-localized cue that initiates polarity establishment was not known.

In addition to the centrosomes, the accurate establishment of the cell polarity requires the precise activity of the actomyosin network, which forms the cytoskeleton. Prior to fertilization in the one-cell embryo, the entire one-cell embryo cell surface undergoes a contraction and relaxation cycle. The centrosome-localized signal causes local inhibition of the actomyosin network near the centrosomes leading to a break in symmetry. This helps in the formation of anterior and posterior domains of partition defective proteins (PARs) (Figure 1). However, the link between the centrosome and cortical contractility also remained elusive.

Figure 1. Working model for the polarity establishment event in the one-cell embryo. (A) Before symmetry breaking the anterior PAR proteins (aPARs in magenta) are distributed throughout the cell cortex. However, at the time of polarity establishment centrosome-based cue helps in promoting the posterior PAR proteins (pPARs in green) localization at the posterior cortex. (B) Before symmetry breaking actomyosin network is distributed throughout the cell cortex; however, centrosome-based signal helps in initiating flow of actomyosin network from posterior to the anterior cortical region.

In our study, we reveal that depletion of the conserved mitotic kinase, Aurora A kinase (AIR-1 in C. elegans), using RNA interference (RNAi) in the one-cell embryo disrupts the stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin dynamics leads to the formation of two posterior polarity axes (Figure 2) instead of one.

Figure 2. Anterior and posterior PAR distribution (A, B); Myosin and pPAR distribution (C, D); and cortical membrane behaviour (E, F) in control and Aurora A (RNAi) embryos

Notably, this impact of Aurora A depletion is independent of its central function in microtubule nucleation i.e. formation of microtubules at the centrosome. Interestingly, centrosomes positioning in dictating the posterior polarity axis (or PAR-2 localization) is no longer in action when Aurora A is depleted in one-cell embryos. Additionally, we observed rescue in the formation of a single polarity axis in Aurora A (RNAi) embryos when another important regulator of actomyosin network, a Rho-GEF called ECT-2, is co-depleted with Aurora A.

In summary, our study has contributed in uncovering an unconventional role of Aurora A kinase gradient at the centrosome in ensuring proper polarity set-up. Since Aurora A is an evolutionarily conserved gene, it is possible that Aurora A kinase function in modulating actomyosin-based cortical contractility is relevant to various biological themes across various cell types. 

References:

Centrosome Aurora A regulates RhoGEF ECT-2 localisation and ensures a single PAR-2 polarity axis in C. elegans embryos. Sukriti Kapoor and Sachin Kotak. Development. November 2019.