of the Max - MDC

Molecular Control of Central
and Peripheral Nervous System
Development
Stefan Britsch
(Helmholtz Fellow)
The ability of the mature nervous system to integrate, compute, and distribute information results from developmental
processes that create diversity, connectivity, and the spatial organization of neurons. Our group is interested
in understanding the molecular mechanisms and regulatory networks, which orchestrate the ordered spatiotemporal
appearance of these developmental events. Current research from our group focuses on the systematic
identification and functional characterization of genes involved in the molecular control of diversification, circuit
formation and spatial organization of neurons in the central nervous system. To address this we combine systematic
genomic screens with gain-/loss-of-function studies in vivo and in vitro. By the help of this strategy, we have
recently identified several novel candidate genes, and demonstrated that one of these factors, the Krüppel-C 2 H 2
zinc finger transcription factor Bcl11a, has a key role in morphogenesis and circuit formation in neurons of the central
nervous system.
Genomic and functional analysis of dorsal spinal
cord development
The dorsal spinal cord is a major processing center that
integrates somatosensory information, like touch, pain,
temperature and proprioception, and relays it to secondary
brain centers. These functions reside in a large number of
diverse interneuron populations located in the dorsal spinal
cord. Sensory interneurons can modulate, enhance, and
even – in the case of central pain control – suppress sensory
input. Spinal sensory interneurons have been characterized
by their physiological and morphological properties, and by
their laminar position in the dorsal horn. However, the
molecular mechanisms that control their differentiation and
functional integration into complex neuronal circuits are
incompletely understood. To identify candidate genes, with
putative functions in the development of the dorsal spinal
cord, we have performed a differential genomic screen with
high-density oligonucleotide microarrays. By comparison of
expression profiles of ventral and dorsal spinal cords, we
identified genes that are enriched in the dorsal neural tube.
Included among the differentially expressed genes are
those with known functions in spinal cord development, as
well as other genes with as yet unknown functions. Within
this group of genes we have identified the homeodomain
transcription factor Gbx1 and two Krüppel-C 2 H 2 zinc finger
transcription factors, Bcl11a and Bcl11b.
Recent work from our group has demonstrated that Gbx1 is
expressed specifically in a subset of Lbx1 + (class B) neurons
in the dorsal spinal horn. Expression of Gbx1 in the dorsal
spinal cord depends on Lbx1 function. Gbx1 identifies a
distinct population of late-born, Lhx1/5 + , Pax2 + neurons.
In the perinatal period, Gbx1 marks a subpopulation of
GABAergic neurons. The expression of Gbx1 suggests that it
controls the development of a specific subset of GABAergic
neurons in the dorsal horn of the spinal cord. We have generated
loss-of-function mutations of the Gbx1 gene in mice
for further analysis of its role in the developing spinal cord.
Homozygous mutant mice are viable, however, during adolescence
these mice develop neurological symptoms indicating
defective spinal processing of somatosensory information.
Bcl11a and b are closely related C 2 H 2 zinc finger transcription
factors, which have previously been shown to be essential
for the development of B- und T-lymphocytes, respectively.
Furthermore, chromosomal aberrations of Bcl11a and
b have been reported from various lymphoid malignancies
in humans. Both genes are also expressed in the embryonic
brain, spinal cord and peripheral nervous system. There is
emerging evidence that common regulatory mechanisms are
utilized during embryogenesis to control the development
of independent organ systems. This is particularly evident
for the development of the lympho-haemopoietic and the
nervous system. To analyze functions of Bcl11a and b in
nervous system development we have generated CNS-specific
conditional mouse mutants for the Bcl11a and b genes
(collaboration with Neal Copeland, NCI Frederick).
Conditional mutant animals die after birth, indicating that
both genes serve critical functions during nervous system
development. Our phenotype analysis of the Bcl11a mutants
demonstrates that the gene is critical for neuronal morphogenesis,
and circuit formation within the dorsal spinal horn.
Bcl11a is also expressed in other regions of the brain (i.e.
hippocampus, cerebellum). Phenotype analysis of mice with
conditional mutations of Bcl11a restricted to these brain
areas indicates that Bcl11a has similar functions in hippocampal,
and cerebellar neurons as observed for the spinal
156 Function and Dysfunction of the Nervous System