Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development.
Disruption of heparan sulfate (HS) synthesis in vertebrate development causes malformations that are composites of those caused by mutations of multiple HS binding growth factors and morphogens. We previously reported severe developmental defects of the forebrain and the skull in mutant mice bearing a targeted disruption of the heparan sulfate-generating enzyme GlcNAc N-deacetylase/GlcN N-sulfotransferase 1 (Ndst1). Here, we further characterize the molecular mechanisms leading to frontonasal dysplasia in Ndst1 mutant embryos and describe additional malformations, including impaired spinal and cranial neural tube fusion and skeletal abnormalities. Of the numerous proteins that bind HS, we show that impaired fibroblast growth factor, Hedgehog, and Wnt function may contribute to some of these phenotypes. Our findings, therefore, suggest that defects in HS synthesis may contribute to multifactor types of congenital developmental defects in humans, including neural tube defects.
Pallerla
Srinivas R
SR
Institut für Allgemeine Zoologie und Genetik, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Pan
Yi
Y
Zhang
Xin
X
Esko
Jeffrey D
JD
Grobe
Kay
K
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001848:Bone Diseases, Developmental / Q000235:genetics*; D049109:Cell Proliferation; D017931:DNA Primers; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D051379:Mice; D009421:Nervous System Malformations / Q000235:genetics*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015238:Sulfotransferases / Q000378:metabolism*
D017931:DNA Primers; D005346:Fibroblast Growth Factors; D015238:Sulfotransferases; C021350:heparitin sulfotransferase; D000469:Alkaline Phosphatase