(Smooth Brain): A Neural Developmental Disorder
Roles of the Lissencephaly Gene LIS1 in Embryonic Neurogenesis"
to understand the mechanisms of how neuronal cells are
born and how neural stem cells regenerate themselves
in the nervous system during embryonic development is
a key challenge in neural stem cell research. The pathway
by which neuronal cells are born is itself proving to
be complex. In human, as well as other mammals, cortical
neurons are generated by the neural stem cells lying
in the innermost zone of the cerebrum. During proliferation,
these neural stem cells exhibit a characteristic yet
mysterious pattern of nuclear oscillation within this
zone (a). The neuronal cells, consequently, undergo
a series of morphological changes (b) and migrate to
the outer layer of the cerebrum (c) where most of the
neuronal cells reside throughout life and form the highly
organized cerebral cortex (d). The complex transformation
in morphology and motility involves at least hundreds
of genes and dramatic changes in structural organization
within the cells at different stages. To date, only
a few genes are identified to control and regulate the
progression of this neurogenesis pathway. The requirement
for this complex morphological changes and how it is
controlled by these genes also remains largely unexamined.
work has emerged from my interest in the human LIS1
gene, mutations in which result in a relatively common
(~1 in 100,000 live births) severe congenital cortical
disorder, lissencephaly (smooth brain disease), to study
neural stem cells under normal and disease conditions
through the entire neurogenesis pathway. We are testing
the effects of down-regulating this gene on neural stem
cell division and neuronal migration. Our results have
demonstrated numerous exciting and important effects
at each step along the entire neurogenesis pathway.
We observed, along with many other novel findings, a
complete block in nuclear oscillations within neural
stem cells (a'). Surprisingly, the cell division is
also abolished, suggesting the nuclear oscillation is
necessary for neural stem cell division. This effect
sheds important new light on the very long-standing
issue of the relationship between nuclear position and
cell cycle, and strongly argues that some spatial cues
may control neural stem cell division.
our observations identified the lissencephaly gene LIS1
as one of the first genes potentially involved in neural
stem cell division, morphogenesis (b'), fate determination,
and neuronal migration (c'), a phenomenon of considerable
interest in understanding normal brain development,
and how to control the proliferation and repopulation
of the brain by neural stem cells. We are currently
searching for other potential genes that involve in
embryonic neurogenesis and investigating their functions
in this pathway. By understanding the mechanisms of
neurogenesis pathway, we may, ultimately, be able to
control the proliferation and production of neural stem
cells in both embryonic and adult nervous system and
apply this knowledge to their possible therapeutic use.
Journal of Cell Biology features our research on
the lissencephaly gene LIS1
Neural stem cells go through a complex process of morphogenesis
and migration to produce neurons
from scholars in this field:
manuscript by Tsai et al. is a tour de force analysis
of a controversial issue in developmental neurobiology...
the authors use a variety of elegant approaches... to demonstrate
that LIS1 and dynactin act as regulators of dynein during
cortical histogenesis." -Prof.
Mary E. Hatten, Rockefeller
remarkable original paper combines multiple approaches
to demonstrate that Lis1 not only controls neuronal motility
but also neuronal precursor cell cycle in the cortical germinative
zone, potentially linking cell division with cell migration."
-Dr. Pierre Gressens, Inserm; Paris 7 University; Robert Debre
unusually high enthusiasm." -Prof.
Don W. Cleveland, Univ.
of California, San Diego; Editor, The
Journal of Cell Biology
beautiful paper." -Prof.
Li-Hui Tsai, Harvard
M. Elizabeth Ross, Weill
Medical College of Cornell Univ.
interesting work." -Prof.
Orly Reiner, Weizmann
Inst. of Science, Israel
John D. Koester, Columbia
Chi-Hung Lin, Natl.
Yang-Ming Univ., Taiwan
Prof. Kevin T. Vaughan, Univ.
of Notre Dame
work is so well done and thought of." -Dr. Manjari
Mazumdar, Research Fellow, National
Institute of Health
updated 6/13/2013. Copyright© 2005 Jin-Wu
Tsai. All rights reserved.