Development 134 (2)
IN THIS ISSUE
Hemangioblasts are precursor cells that have the
ability to differentiate into either haematopoietic or
endothelial cells. However, the precise molecular
events that give rise to these lineages and to the hemangioblast itself remain
unclear. To determine the molecular signature of the hemangioblast and to
identify factors that direct these cells to differentiate, Lugus et al. compared the
gene expression profiles of embryonic stem cell-derived hemangioblasts to
their differentiated progeny. On p. 393, the authors reveal how Gata2
transcripts are enriched in the hemangioblast cell population in comparison
with other stem cell populations, and how GATA2 forms part of a positive
feedback loop with BMP4. They further reveal how enforced early GATA2
expression in hemangioblasts leads to increased numbers of erythroid and
endothelial progeny. Later expression leads to the development of larger
erythroid colonies, which occurs independently of the hemangioblast.
Whether GATA2 has further cell-type-specific roles in other developmental
processes remains to be determined.
Indian hedgehog signalling given
a lIFT
Cilia are present on most cells of the body and their
formation depends on intraflagellar transport (IFT).
Mutations that affect IFT lead to altered sonic
hedgehog (Shh) signalling, and consequently to limb
and neural tube patterning defects in mice. Now, on
p. 307, Bradley Yoder and co-workers reveal for the first time that IFT and
therefore cilia are also required for normal Indian hedgehog (Ihh) signalling.
They made their discovery using a conditional allele of an IFT protein,
IFT88/polaris, to disrupt cilia and to investigate the effects on mouse limb
development. Although cilia disruption in the ectoderm produces no
phenotype, disruption in the mesenchyme results in polydactyly, a loss of
anteroposterior digit patterning and a shortening of the proximodistal axis of
the limb. Their results show that the digit-patterning phenotypes are associated
with disrupted Shh activity. The limb outgrowth defects, however, are due to
abrogated Ihh signalling during endochondral bone formation, the first
evidence that IFT and normal cilia functioning are required for Ihh signalling.
Polarising neurons: enter NAB-1
The correct establishment of either an axon or a
dendrite is crucial for the normal wiring of a
functional nervous system. As previously shown, the
SAD serine-threonine kinases are required for such
neuronal polarisation and also for the clustering of
synaptic vesicles at neuromuscular junctions. Mei
Zhen and colleagues now shed further light on how SAD functions in neuronal
polarisation (see p. 237). From a yeast two-hybrid screen in C. elegans,
performed to isolate mediators of SAD-1 function, the authors identified
Neurabin (NAB-1) and show that it physically interacts with SAD-1 in vivo and
in vitro. Double sad-1 nab-1 mutants, they report, have polarity defects, in
which synaptic vesicles cluster in both axons and dendrites. However, only nab1 mutants have normal vesicle cluster morphology. The authors propose that
NAB-1 acts as a scaffold for SAD-1, interacting with SAD-1 via PDZ domains.
Mammalian neurabins are required for dendrite spine maturation, but whether
they also have an earlier role in axon determination, as in C. elegans, remains
to be determined.
Targeting Hox targets
Hox transcription factors have a welldocumented role in morphogenesis along the
anteroposterior axis. They are expressed colinearly along the body axis and regulate specific
downstream targets via their conserved DNA-binding homeodomain. But only
a small number of their transcriptional target genes have so far been identified.
On p. 381, Hueber et al. report the identification of potentially hundreds of
new Hox targets from a microarray analysis designed to identify the targets of
six Drosophila Hox proteins. The authors validated many of these targets by in
situ hybridisations in different genetic backgrounds, and interestingly reveal
how most targets are regulated by a specific Hox protein. Many of the
identified genes have known functions in processes such as apoptosis, cell
migration and cell-cell adhesion. For example, skl, an apoptotic activator, is
identified as a target of the Hox protein Deformed (Dfd), and has reduced
expression in Dfd mutants, accompanied by reduced apoptosis. Many targets
encode transcription factors, such that Hox factors appear to regulate
morphogenesis indirectly.
␤-Spectrin holds the line
␣- and ␤-Spectrins connect actin filaments of the
cytoskeletal network to integral plasma membrane
proteins and have structural roles in red blood cells, and
also in protein targeting and membrane formation in
non-erythroid cells. On p. 273, Greg Bashaw and
colleagues demonstrate a role for ␤-Spectrin in repulsive midline axon
guidance and in the maintenance of axon connections in the Drosophila
embryonic CNS. In ␤-Spectrin mutant embryos, axons inappropriately cross the
midline; however, these defects are rescued by expressing a form of ␤-Spectrin
that carries mutated Ankyrin and Plekstrin Homology (PH) domains, indicating
that axon repulsion occurs independently of these domains. ␤-Spectrin may
contribute to Slit-Robo-mediated axon repulsion during growth cone
migration, as a dose-dependent genetic interaction is demonstrated between
␤-Spectrin and the Slit-Robo pathway. As such, ␤-Spectrin could, the authors
speculate, play a key role in maintaining the membrane domains that contain
guidance molecules, providing a link between the signalling pathways involved
and membrane dynamics.
A hair-raising choice for Gata3
The hair follicle is composed of the hair shaft and
epithelial stem cells, which can repopulate hair
follicles if an inductive signal is received from the
surrounding dermal papilla. Gata3 is known to be
involved in hair follicle and epidermis
differentiation, but precisely how remains unclear. Now, Kurek and coworkers reveal that Gata3 integrates different signalling networks and is
crucial in regulating the choice between forming the different layers of the
hair follicle and maintaining the epidermis. On p. 261, the results of a
comparative transcriptional assay designed to identify upregulated genes in
Gata3 mutant hair follicles reveal that increases in Notch, Wnt and BMP
pathway components occur in the absence of Gata3, while genes associated
with cell cycle progression and apoptosis are downregulated. In the absence
of Gata3, hyperproliferation occurs in the basal epidermal cells at the expense
of correct hair follicle development. The authors propose that Gata3 acts a
moderator between hair follicle development and epithelial cell
differentiation.
DEVELOPMENT
GATA2 and BMP4: determining
haematopoietic fates