Structural bases of asymmetric cell division

Research project

We are interested in the molecular mechanisms that govern mitotic spindle orientation in asymmetric cell divisions.

In asymmetric cell divisions the mother cell gives rise to two daughters with different fate. This is crucial for generating diversity during development and for the function of self-renewing stem cells. A prerequisite for asymmetric divisions is the establishment of a polarity axis that guides the localization of fate determinants towards specific cellular regions. Subsequent spindle coupling to the polarity axis positions the cleavage plane such that the fate determinants are unequally partitioned between the two daughter cells. We study the molecular mechanisms contributing to integrate the cellular polarization signals with the spindle position in order to allow the correct asymmetric outcome of a cell division.

Fig. 1: Coordination of spindle orientation with cell polarity [+zoom]

Spindle orientation requires pulling forces exerted by cortical force generators on astral microtubules emanating from the spindle poles. A fascinating hypothesis envisions these force generators as adaptors anchored at specific sites of the cortex and retaining interaction with depolymerizing microtubules, whose shrinkage would pull towards the cortex the connected spindle pole. Emerging evidence has pointed at the evolutionary conserved NuMA/LGN/Gαi pathway as the major machinery responsible for cortical force generation. In polarized mitoses NuMA/LGN/Gαi complexes assemble at cortical crescents underlying the spindle poles to drive both the activation of a non-canonical G-protein signaling cascade and the recruitment at the cortex of the microtubule motor dynein (/Figure 1/).
We aim at understanding how specific interactions between proteins of the the NuMA/LGN/Gαi pathway orchestrate the generation of microtubule pulling forces. In addition, we are interested in learning how the NuMA/LGN/Gαi network cooperates with less conserved pathways relevant for spindle orientation in specific cellular systems.

To obtain molecular insights into processes underlying spindle coupling, we use structural biology approaches (x-ray crystallography) in combination with biochemical and biophysical methods. We also collaborate with cell biologists to test hypotheses formulated on the basis of structural and functional information.