Lis1 (green) accumulates at the nuclear envelope and helps control its breakdown.

Before chromosomes can go their separate ways during mitosis, the nuclear envelope has to dissolve. As Hebbar et al. reveal, breakdown of the membrane might influence the fate of cells in the developing brain by controlling when they divide.

The ventricular zone is the developing brain's maternity ward, where stem cells give birth to neurons and other cell types. Within these stem cells, nuclei continually move up and down, and their position when division occurs helps settle the fate of the progeny. One daughter cell will always become a replacement stem cell, but the second daughter will typically become a neuron if cell division occurs when the nucleus is at the top of the cell, or will likely become another type of precursor if the nucleus is at the bottom. Changing the timing of division could alter the progeny's fate because the nucleus might be at a different position.

Hebbar et al. discovered that the breakdown of the nuclear envelope helps determine division's onset. The researchers were studying two proteins essential for normal brain development, Lis1 and Ndel1, which latch onto each other and then grab dynein, a motor protein. Several years ago, scientists revealed that dynein spurs formation of pockets on one side of the nucleus, stressing the nuclear envelope and causing it to tear and eventually disintegrate. Hebbar et al. showed that the amount of Lis1 and Ndel1 in the cell can accelerate or slow formation of these pockets.

The team also discovered that phosphorylation of Ndel1 flips the switch for pocket formation, dislodging Lis1 and Ndel1 from dynein. That might unleash the motor protein to dent the nuclear envelope.

When they examined embryonic mice that carry half the normal amount of Lis1, the scientists found that stem cells from the animals' ventricular zone showed fewer pockets and delayed nuclear envelope disintegration. Such a slowdown could be disastrous for the developing brain. It could cause the cells to divide at the wrong point in their oscillations, triggering an overproduction of neurons and eventual depletion of stem cells. In fact, previous work has shown that this mouse strain produces neurons at the expense of precursors.

Previous studies indicated the orientation of the mitotic spindle determines cell fate, but the work suggests nuclear envelope breakdown, which occurs before the spindle gets into position, contributes to the decision.

Hebbar, S., et al.
J. Cell Biol.