Modifikation von Heparansulfaten: Die Funktion sezernierter Sulfatasen im Transport von Indian Hedgehog während der endochondralen Ossifikation
Final Report Abstract
Modification of the sulfation pattern of heparan sulfate (HS) during organ development is thought to regulate binding and signal transduction of several growth factors. Here we have identified and investigated 14 mouse sulfatase genes that remove sulfate groups from the HS chains either during degradation or in the extra cellular matrix. Expression analysis identified a complex overlapping pattern in many tissues especially the extremities and the central nervous system. We have concentrated our functional analysis on the secreted sulfatases, Sulf1 and Sulf2, which act as extracellular HS 6-O-endo sulfatases. We show that both sulfatases are expressed in overlapping patterns during embryonic skeletal development. Analysis of compound mutants of Sulf1 and Sulf2 derived from gene trap insertions and targeted null alleles revealed subtle but distinct skeletal malformations including reduced bone length, premature vertebrae ossification and fusions of sternebrae and tail vertebrae. Molecular analysis of endochondral ossification points to a function of Sulf1 and Sulf2 in delaying the differentiation of endochondral bones. Penetrance and severity of the phenotype increased with reduced numbers of functional alleles indicating redundant functions of both sulfatases. The mild skeletal phenotype of double mutants suggests a role for extracellular modification of 6-O-sulfation in fine-tuning rather than determining the development of skeletal structures.
Publications
- (2008). Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. Dev Dyn 237, 339-353
Ratzka, A., Kalus, I., Moser, M., Dierks, T., Mundlos, S., and Vortkamp, A.
- (2008). Untersuchung zur Funktion der 6-O-Endosulfatasen Sulf1 und Sulf2, während der Skelettentwicklung am Mausmodell. Promotionsschrift
Ratzka, A.
- (2010). Expression patterns of sulfatase genes in the developing mouse embryo. Dev Dyn 239, 1779-1788
Ratzka, A., Mundlos, S., and Vortkamp, A.
