First published online January 12, 2006
Development 133, 301e (2006)
© The Company of Biologists Limited
Hedgehog: a low cholesterol spread?
Hedgehog (Hh) is a crucial regulator of development that acts over short
and long ranges to control cell fate decisions. How Hh spreads to form a
signalling gradient is particularly intriguing because active Hh is lipid
modified (it carries cholesterol and palmitoyl adducts), and lipid-modified
proteins are usually membrane tethered. Previous findings about the role of
lipid modification in Hh signalling have been contradictory, with results
differing in particular between vertebrates and Drosophila. Now two
papers shed light on these events but also raise more questions. On
p. 471, Callejo and
colleagues report that lipid modification is required for Hh to interact with
heparan sulphate proteoglycans (HSPGs). This interaction, they report,
restricts the spread of lipid-modified Hh in the fly wing disc and leads to
the activation of high Hh threshold response genes, perhaps with HSPGs acting
as a co-receptor. Unlipidated Hh forms more extensive gradients, spreading for
many more cell diameters than lipidated Hh and inducing the same low
threshold-response genes as lipidated Hh, independently of HSPGs. The two Hh
forms are also internalised differently – lipidated Hh laterally and
unlipdated Hh through the apical membrane. Together, these results indicate
that lipid modification plays a conserved role in Hh signalling by affecting
multimerisation, Hh spreading and signalling activity. On
p. 407, Gallet et al.
also conclude that Hh lipid modification serves this conserved role but from
quite different results. These authors compared the behaviour of lipidated Hh
with that of a truncated, cholesterol-free (Hh-N) form in Drosophila
embryonic ectoderm and imaginal disc tissue. The absence of cholesterol, they
report, affects the secretion of Hh, its multimerisation and also,
intriguingly, its long-range signalling activity. For example, distant cell
types in the dorsal ectoderm, which require low Hh levels, are absent in
Hh-N-expressing embryos, indicating that the range of activity of Hh-N is
limited. From these and other results, the authors propose that cholesterol
modification is required for the controlled planar movement of Hh to prevent
its unrestricted spreading. Future experiments should resolve how lipid
modification affects the precise range and activity of Hh in different fly
tissues and the degree to which such events are conserved.
Related articles in Development:
- Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia
- Armel Gallet, Laurent Ruel, Laurence Staccini-Lavenant, and Pascal P. Thérond
Development 2006 133: 407-418.
[Abstract]
[Full Text]
- Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix
- Ainhoa Callejo, Carlos Torroja, Luis Quijada, and Isabel Guerrero
Development 2006 133: 471-483.
[Abstract]
[Full Text]
