The step by step differentiation of embryonic cells into different types of
neurons lays the foundation for our sensory responses, motor commands, and cognitive
behaviors. Our research explores this exquisite differentiation program in mammals
using a combination of genetic, embryological, and molecular biological methods.
While the generation of such neural diversity is a complex process culminating
in the most sophisticated of wiring circuits, one simplifying approach is to
start by tracking the specification, differentiation, and migration paths taken
by specific sets of cells originating from primitive neuroectoderm. Towards
this goal, our lab has generated a variety of recombinase-based tools to study
progenitor-progeny cell relationships in the mouse. We are applying these and
other molecular genetic and genomic tools to study programs underlying the functional
and anatomical patterning of neuronal assemblies in the brain stem, paying particular
attention to development of the precerebellar system (with its central role
in movement control and sensorimotor transformations), the serotonergic system
(with its involvement in such disparate functions as sleep, arousal, homeostasis,
pain, and depression), and the choroid plexus (as an organizing/patterning center
during embryogenesis and as the source of cerebral spinal fluid).
The lab has considerable expertise in conditional genetic technologies and is
continually developing new tools by which to explore development and gene function.
One current effort involves establishing a set of enabling reagents for constructing
functional connectivity maps of the mouse brain and spinal cord.
In addition to studying neural development, we have initiated genetic experiments
to uncover more general determinants of tissue pattern. Using insertional mutagenesis,
we have created mutant mouse stocks that exhibit developmental defects ranging
from skeletal abnormalities to hair and thymic defects. We are currently using
large-insert DNA clones that span the transgene insertions to identify the affected
genes. Through this approach, we have identified a BMP receptor that is the
physiologic transducer mediating the development of digit cartilages. Transcriptional
regulation of this gene has proven to be interesting and may represent a driving
force in the evolution of distal limb form.