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32 | DEVELOPING PEOPLE
Brain power
Inner secrets
What links tadpoles, flies’ wings, seahorses and the
human brain? A remarkable protein called Lhx2.
Computer analysis can reveal key
regulatory features in the genome.
1 2 3
How do cells form integrated
structures during development?
Since Hans Spemann’s classic work
on tadpoles in the 1920s it has been
known that certain cells can direct the
fate of those around them, organising
them into a specific structure. Now,
former International Senior Research
Fellow Shubha Tole and colleagues
have identified a key gene, Lhx2, that
controls development of the cerebral
cortex and the hippocampus – a
seahorse-shaped structure crucial to
memory formation.
Lhx2 is a relative of a protein involved in
fruit-fly wing development. Rather than
wings, in mammals Lhx2 has been
thought to be a key specifier of cerebral
cortex. During development, it is found in
cells that become the cerebral cortex but
not in an adjacent strip, known as the
hem, present at the edge of the cortex.
By clever genetic engineering of mice, Dr
Tole and colleagues were able to turn
Lhx2 gene activity on and off in particular
regions of the brain and at particular
times of development. They discovered
that Lhx2 is essential for specification of
the cerebral cortex. It also prevents
these cells from turning into hem cells –
thereby ensuring that the hem is formed
only at the very edge of the cortex.
When Lhx2 was turned off in patches of
cortical cells, however, these cells
became hem cells even though they
were in the middle of the cortex. And
next to each extra hem, a new
hippocampus was formed from cells that
would have otherwise become part of other
cortical regions. This implies that the hem
is an organiser that directs adjacent
cortical cells to form the hippocampus.
This role of Lhx2 is not the only trick in its
book. Dr Tole’s group has found that it is
also involved in the early growth of
nerves carrying sensory information to
the cortex. In fact, it is also needed for
development of the olfactory bulb, a key
structure in rodents’ sense of smell.
It is also active in a stream of cells that
helps to build the amygdala, a structure
central to the processing of emotional
information. This stream of cells
originates from the same region that also
gives rise to the cerebral cortex,
revealing an unsuspected link between
development of the amygdala and the
cortex.
Mangale VS et al. Lhx2 selector activity specifies
cortical identity and suppresses hippocampal
organizer fate. Science 2008;319(5861):304–9.
Saha B et al. Dual role for LIM-homeodomain gene
Lhx2 in the formation of the lateral olfactory tract. J
Neurosci 2007;27(9):2290–7.
Remedios R et al. A stream of cells migrating from the
caudal telencephalon reveals a link between the
amygdala and neocortex. Nat Neurosci
2007;10(9):1141–50.
With ever more genome sequence
being generated, a major challenge is
to identify biologically important
regions. These include the regulatory
sequences that control the activity of
genes. Thomas Down, a new
Research Career Development Fellow
at the Gurdon Institute in Cambridge,
is developing software tools that trawl
genomic data and identify possible
control regions.
A major surprise emerging from the
Human Genome Project was the
relatively small number of genes encoded
within the genome. The biological
complexity of humans is thus down to not
just the number of components from
which we are made but also how those
components are used. While 1.5 per cent
of the genome codes for genes, around 5
per cent appears to be under strong
selective pressure, and many of these
conserved sequences are likely to be
regulatory elements that control where
and when genes are active.
As a PhD student at the Wellcome Trust
Sanger Institute at Hinxton, Dr Down
combined his interests in biology and
computing to develop software tools to
aid the analysis of genome sequence
data. These have included tools to
identify distinctive sequence motifs
associated with promoters – the primary
regions driving gene activity. Testing one
Images
1 Tracking gene activity in populations of cells in the brains of Lhx2
mutant mice.
2 T h e Lhx2 gene plays a key role in building the mammalian cortex.
3 Thomas Down of the Gurdon Institute.
4 Drops of water on the pins of a liquid-handling device.
5 Mairead MacSweeney of University College London.
6 Identifying areas of the brain responding to sign language.