Projects per year
Abstract / Description of output
The corpus callosum (CC) connects the left and right cerebral hemispheres in mammals and its development requires intercellular communication at the telencephalic midline mediated by signaling proteins. Heparan sulfate (HS) is a sulfated polysaccharide that decorates cell surface and extracellular matrix proteins and regulates the biological activity of numerous signaling proteins via sugar-protein interactions. HS is subject to regulated enzymatic sulfation and desulfation and an attractive, although not proven, hypothesis is that the biological activity of HS is regulated by a sugar sulfate code. Mutant mouse embryos lacking the heparan sulfotransferases Hs2st or Hs6st1 have severe CC phenotypes and form Probst bundles of noncrossing axons flanking large tangles of midline glial processes. Here, we identify a precocious accumulation of Sox9-expressing glial cells in the indusium griseum region and a corresponding depletion at the glial wedge associated with the formation of Probst bundles along the rostrocaudal axis in both mutants. Molecularly, we found a surprising hyperactivation of Erk signaling in Hs2st(-/-) (2-fold) and Hs6st1(-/-) (6-fold) embryonic telencephalon that was most striking at the midline, where Erk signaling is lowest in wild-types, and a 2-fold increase in Fgf8 protein levels in Hs6st1(-/-) embryos that could underpin Erk hyperactivation and excessive glial movement to the indusium griseum. The tightly linked Hs6st1(-/-) CC glial and axonal phenotypes can be rescued by genetic or pharmacological suppression of Fgf8/Erk axis components. Overall, our data fit a model in which Hs2st and Hs6st1 normally generate conditions conducive to CC development by generating an HS-containing environment that keeps Erk signaling in check.
Original language | English |
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Pages (from-to) | 2389-401 |
Number of pages | 13 |
Journal | Journal of Neuroscience |
Volume | 34 |
Issue number | 6 |
DOIs | |
Publication status | Published - 5 Feb 2014 |
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Dive into the research topics of 'Heparan sulfotransferases hs6st1 and hs2st keep erk in check for mouse corpus callosum development'. Together they form a unique fingerprint.Projects
- 4 Finished
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Regulation of the genome by the transcription facto Pax6 during brain development
1/06/12 → 31/12/16
Project: Research
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The Functions of the transcription factor Pax6 in thalamic neurona
Price, D., Mason, J. & Pratt, T.
1/01/09 → 30/06/14
Project: Research
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Mechanisms for regulating mammalian axon guidance by differential sulphation of heparan sulphate
Pratt, T., Mason, J. & Price, D.
13/10/08 → 12/01/12
Project: Research
Profiles
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Thomas Pratt
- Deanery of Biomedical Sciences - Senior Lecturer
- Centre for Discovery Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active