|
MUTATIONS
OF THE HOMEOBOX GENE DLX-1 AND DLX-2 DISRUPT THE STRIATAL SUBVENTRICULAR
ZONE AND DIFFERENTIATION OF LATE-BORN STRIATAL NEURONS. Stewart Anderson,
Nina Ireland Laboratory of Developmental Neurobiology, University of California,
San Francisco 94143-0984, USA.
The striatum
plays a key role in normal brain function and in a number of disease processes,
yet the molecular control of its development remains obscure. Recently,
progress has been made due to the discovery of transcription factors, such
as the Dlx genes, whose expression patterns suggest that they are important
regulators of striatal development. Indeed, mice lacking both Dlx-1 and
Dlx-2 have a time-dependent block in migration out of the striatal
proliferative zones. Histological analysis of the Dlx-1/Dlx-2 mutant striatum
on the day of birth (P0; also the day these mutants die) reveals an abnormal
periventricular region of undifferentiated appearing cells, and a striatum-like
region that is enriched for markers of the striatal patch compartment.
Interestingly, the mutant periventricular region contains an abnormal overlap
of dividing cells and cells immunoreactive for the post-mitotic neuronal
marker, MAP2. This abnormality is first detectable at embryonic day 13.5
(E13.5). Two methods were used to determine that post-mitotic cells begin
accumulating in the mutant striatal proliferative zone during the latter
part of embryonic development. First, BrdU birthdating experiments revealed
that cells born at E11.5 migrate into the differentiated portion of the
mutant striatum by P0. However, most cells labeled at E15.5 remain within
the mutant proliferative zone. Second, the study of migrating cells in
slice cultures produced a similar result. The development of this migration
abnormality in the Dlx-1/Dlx-2 mutants correlates with the emergence of
the subventricular zone (SVZ) as the dominant proliferative population
within the striatal anlage. In addition, the expression of several transcription
factors is absent or abnormal in the mutant SVZ. These results suggest
that differentiation within the striatal SVZ is disrupted in the mutants,
and support the hypothesis that the striatal matrix compartment derives
from the SVZ.
[Abstract Titles] [Bolz] [Chugani] [Levitt] [Olson] [Zhou]
|
|
|