Mammalian Brain Morphogenesis and Midline Axon Guidance Require Heparan Sulfate

Inatani, Masaru; Irie, Fumitoshi; Plump, Andrew S.; Tessier‐Lavigne, Marc; Yamaguchi, Yu

doi:10.1126/science.1090497

Cited by 384 publications

(341 citation statements)

References 18 publications

(13 reference statements)

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“…As those factors also play critical roles in morphogenesis, growth regulation, and differentiation, defective HS synthesis affects multiple aspects of vertebrate development. Mice deficient in Ext1, Ndst1, 2-Ost, and GlcA C5-epimerase function have defective brain morphogenesis, axon guidance defects, craniofacial defects, renal agenesis, and eye defects due to the simultaneous inhibition of multiple HS binding factors (Bullock et al, 1998;Inatani et al, 2003;Li et al, 2003;McLaughlin et al, 2003;Grobe et al, 2005). Here, we report additional developmental defects of the skeleton and the developing head in Ndst1-deficient embryos resulting from impaired function of Hh, Fgf, and possibly Wnt.…”

Section: Introductionmentioning

confidence: 65%

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Pallerla

Pan

Zhang

et al. 2006

Developmental Dynamics

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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 Nsulfotransferase 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. Developmental Dynamics 236: 556 -563, 2007.

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Section: Introductionmentioning

confidence: 65%

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Pallerla

Pan

Zhang

et al. 2006

Developmental Dynamics

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“…Taken together, although the chlorate result highlights the general importance of endogenous sulfation, the siRNA results suggest that specific HSPG sulfation patterns modulate NRG1-heparan sulfate interactions important for NRG1 localization and activation. Further analyses of mice with disruptions in genes that regulate heparan sulfation (3,44,45) will be important next steps in examining these NRG1-HSPG interactions in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Heparan sulfate proteoglycans (HSPGs) 1 are ubiquitous components of the cell surface and extracellular matrix that are critical for normal development and regulation of cell growth (1)(2)(3). HSPGs have been implicated in a wide range of biological processes including cell adhesion, motility, proliferation, differentiation, tissue morphogenesis, and carcinogenesis (4,5).…”

mentioning

confidence: 99%

Specific Structural Features of Heparan Sulfate Proteoglycans Potentiate Neuregulin-1 Signaling

Pankonin

Gallagher

Loeb

2005

Journal of Biological Chemistry

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Neuregulins are a family of growth and differentiation factors that act through activation of cell-surface erbB receptor tyrosine kinases and have essential functions both during development and on the growth of cancer cells. One alternatively spliced neuregulin-1 form has a distinct heparin-binding immunoglobulin-like domain that enables it to adhere to heparan sulfate proteoglycans at key locations during development and substantially potentiates its activity. We examined the structural specificity needed for neuregulin-1-heparin interactions using a gel mobility shift assay together with an assay that measures the ability of specific oligosaccharides to block erbB receptor phosphorylation in L6 muscle cells. Whereas the N-sulfate group of heparin was most important, the 2-O-sulfate and 6-O-sulfate groups also contributed to neuregulin-1 binding in these two assays. Optimal binding to neuregulin-1 required eight or more heparin disaccharides; however, as few as two disaccharides were still able to bind neuregulin-1 to a lesser extent. The physiological importance of this specificity was shown both by chemical and siRNA treatment of cultured muscle cells. Pretreatment of muscle cells with chlorate that blocks all sulfation or with an siRNA that selectively blocks N-sulfation significantly reduced erbB receptor activation by neuregulin-1 but had no effect on the activity of neuregulin-1 that lacks the heparin-binding domain. These results suggest that the regulation of glycosaminoglycan sulfation is an important biological mechanism that can modulate both the localization and potentiation of neuregulin-1 signaling.

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“…Thus, it is not surprising that many HS-deficient animals show defects in axonal guidance and sorting (Inatani et al, 2003;Bulow and Hobert, 2004;Lee et al, 2004). Similarly, mouse Sulf have a role in neurite sprouting in embryonic esophagus (Ai et al, 2007).…”

Section: Expression Profile Of Hs Enzymes In Zebrafishmentioning

confidence: 99%

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

Gorsi

Whelan

2010

Developmental Dynamics

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The 6-O-endosulfatase enzymes (Sulfs) edit the final sulfation pattern and function of heparan sulfate (HS) by removal of 6-O-sulfate groups from the chain. To date, two mammalian sulf genes have been identified that regulate many signalling pathways during embryonic development. In zebrafish a sulf1 ortholog and duplicate copies of the mammalian sulf2 gene, sulf2a and sulf2, have been identified, which contain conserved motifs characteristic of vertebrate sulf genes. Zebrafish sulf1 and sulf2a are broadly expressed in the central nervous system (CNS) and non-neuronal tissue including heart, somite boundaries, olfactory system, and otic vesicle, whereas sulf2 expression is almost entirely restricted to the CNS. The duplicate copies of sulf2 have distinct expression patterns, which together mirror that of mouse sulf2, suggesting duplication in the teleost lineage has been followed by subfunctionalisation, whereby both genes need to be preserved by selection to ensure the ancestral gene's expression profile and function is maintained. Developmental Dynamics 239:3312-3323,

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Mammalian Brain Morphogenesis and Midline Axon Guidance Require Heparan Sulfate

Cited by 384 publications

References 18 publications

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Specific Structural Features of Heparan Sulfate Proteoglycans Potentiate Neuregulin-1 Signaling

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

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