||<p>Stem cells are defined by their ability to make more stem cells, a property known
as self-renewal and their ability to generate cells that enter differentiation. One
mechanism by which fate decisions can be effectively controlled in stem cells is through
asymmetric division and the correct partitioning and inheritance of cell fate determinants.
While hematopoietic stem cells have the capacity to divide through asymmetric division,
the molecular machinery that regulates this process is unknown and whether its activity
is required in vivo remains unclear. Here we show that Lis1, a dynein-binding protein
and regulator of asymmetric division, is critically required for blood development
and for hematopoietic stem cell renewal in fetal and adult life. In particular, conditional
deletion of Lis1 led to a severe bloodless phenotype and embryonic lethality in vivo.
In both fetal and adult mice, loss of Lis1 led to a failure of normal self-renewal,
which included impaired colony-forming ability in vitro and defects in long-term reconstitution
ability following transplantation. As a possible mechanism, we find that the absence
of Lis1 in hematopoietic cells, in part, accelerates differentiation linked to the
incorrect inheritance of cell fate determinants. Furthermore, using a live cell imaging
strategy, we find that the incorrect inheritance of cell fate determinants observed
following the loss of Lis1 is due defects in spindle positioning and orientation.
Finally, using two animal models of undifferentiated myeloid leukemia, we show that
Lis1 is critical for the aberrant cell growth that occurs in cancer. Deletion of
Lis1 both at the early and late stages of myeloid leukemia blocked its propagation
in vivo and led to a marked improvement in survival. Together, these data identify
Lis1 and the directed control of asymmetric division as key regulators of normal and
malignant hematopoietic development.</p>