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2015 ; 10
(10
): e0139853
Nephropedia Template TP
gab.com Text
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English Wikipedia
Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation
during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite
Outgrowth Promoting Functions
#MMPMID26448642
Kalus I
; Rohn S
; Puvirajesinghe TM
; Guimond SE
; Eyckerman-Kölln PJ
; Ten Dam G
; van Kuppevelt TH
; Turnbull JE
; Dierks T
PLoS One
2015[]; 10
(10
): e0139853
PMID26448642
show ga
INTRODUCTION: Sulf1 and Sulf2 are cell surface sulfatases, which remove specific
6-O-sulfate groups from heparan sulfate (HS) proteoglycans, resulting in
modulation of various HS-dependent signaling pathways. Both Sulf1 and Sulf2
knockout mice show impairments in brain development and neurite outgrowth
deficits in neurons. METHODOLOGY AND MAIN FINDINGS: To analyze the molecular
mechanisms behind these impairments we focused on the postnatal cerebellum, whose
development is mainly characterized by proliferation, migration, and neurite
outgrowth processes of precursor neurons. Primary cerebellar granule cells
isolated from Sulf1 or Sulf2 deficient newborns are characterized by a reduction
in neurite length and cell survival. Furthermore, Sulf1 deficiency leads to a
reduced migration capacity. The observed impairments in cell survival and neurite
outgrowth could be correlated to Sulf-specific interference with signaling
pathways, as shown for FGF2, GDNF and NGF. In contrast, signaling of Shh, which
determines the laminar organization of the cerebellar cortex, was not influenced
in either Sulf1 or Sulf2 knockouts. Biochemical analysis of cerebellar HS
demonstrated, for the first time in vivo, Sulf-specific changes of 6-O-, 2-O- and
N-sulfation in the knockouts. Changes of a particular HS epitope were found on
the surface of Sulf2-deficient cerebellar neurons. This epitope showed a
restricted localization to the inner half of the external granular layer of the
postnatal cerebellum, where precursor cells undergo final maturation to form
synaptic contacts. CONCLUSION: Sulfs introduce dynamic changes in HS proteoglycan
sulfation patterns of the postnatal cerebellum, thereby orchestrating fundamental
mechanisms underlying brain development.