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

Pallerla, Srinivas Reddy; Pan, Yi; Zhang, Xin; Esko, Jeffrey D.; Grobe, Kay

doi:10.1002/dvdy.21038

Cited by 54 publications

(47 citation statements)

References 42 publications

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“…Thus, the defective HS-PGs in Ndst1-null condyles would not bind Ihh well (Grobe et al, 2005) and would allow it to diffuse more broadly from its site of synthesis in the pre-hypertrophic zone and elicit broader and even ectopic effects on condylar cell proliferation and ossification, as analysis of our data indicated. It should be noted that this interpretation differs from the conclusion reached in a previous study on Ndst1-null long bone growth plates, in which Ihh diffusion and signaling to the periosteum were actually found to be reduced compared with wild-types (Pallerla et al, 2007). One possible explanation for these differing observations is that, though related structurally and functionally, condylar and long bone growth plates and adjacent tissues may obey different mechanisms.…”

Section: Discussioncontrasting

confidence: 87%

Sulfotransferase Ndst1 is Needed for Mandibular and TMJ Development

et al. 2010

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Heparan sulfate proteoglycans (HS-PGs) regulate several developmental processes, but their possible roles in mandibular and TMJ formation are largely unclear. To uncover such roles, we generated mice lacking Golgi-associated N-sulfotransferase 1 (Ndst1) that catalyzes sulfation of HS-PG glycosaminoglycan chains. Ndst1-null mouse embryos exhibited different degrees of phenotypic penetrance. Severely affected mutants lacked the temporomandibular joint and condyle, but had a mandibular remnant that displayed abnormal tooth germs, substandard angiogenesis, and enhanced apoptosis. In mildly affected mutants, the condylar growth plate was dysfunctional and exhibited thicker superficial and polymorphic cell zones, a much wider distribution of Indian hedgehog signaling activity, and ectopic ossification along its lateral border. Interestingly, mildly affected mutants also exhibited facial asymmetry resembling that seen in individuals with hemifacial microsomia. Our findings indicate that Ndst1-dependent HS sulfation is critical for mandibular and TMJ development and allows HS-PGs to exert their roles via regulation of Ihh signaling topography and action.

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Section: Discussioncontrasting

confidence: 87%

Sulfotransferase Ndst1 is Needed for Mandibular and TMJ Development

et al. 2010

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“…Importantly, reduced MAPK signaling and expression of the DNA-binding factor Erm, an Ets family member, was shown in abnormal lens tissues in Ndst1 null embryos. Additional studies of this gene suggest that hh and Wnt signaling are also affected by the impairment in heparan sulfate synthesis (Pallerla et al, 2007).…”

Section: Fgf Signaling In Lens Differentiation-a Schematic Diagram Ofmentioning

confidence: 99%

Genetic and epigenetic mechanisms of gene regulation during lens development

Cvekl

Duncan

2007

Progress in Retinal and Eye Research

141

124

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Recent studies demonstrated a number of links between chromatin structure, gene expression, extracellular signaling and cellular differentiation during lens development. Lens progenitor cells originate from a pool of common progenitor cells, the pre-placodal region (PPR) which is formed due to a complex exchange of extracellular signals between the neural plate, naïve ectoderm and mesendoderm. A specific commitment to the lens program over alternate choices such as the formation of olfactory epithelium or the anterior pituitary is manifested by the formation of a thickened surface ectoderm, the lens placode. Mouse lens progenitor cells are characterized by the expression of a complement of lens lineage-specific transcription factors including Pax6, Six3 and Sox2, controlled by FGF and BMP signaling, followed later by c-Maf, Mab21like1, Prox1 and FoxE3. Proliferation of lens progenitors together with their morphogenetic movements results in the formation of the lens vesicle. This transient structure, comprised of lens precursor cells, is polarized with its anterior cells retaining their epithelial morphology and proliferative capacity, whereas the posterior lens precursor cells initiate terminal differentiation forming the primary lens fibers. Lens differentiation is marked by expression and accumulation of crystallins and other structural proteins. The transcriptional control of crystallin genes is characterized by the reiterative use of transcription factors required for the establishment of lens precursors in combination with more ubiquitously expressed factors (e.g. AP-1, AP-2α, CREB and USF) and recruitment of histone acetyltransferases (HATs) CBP and p300, and chromatin remodeling complexes SWI/SNF and ISWI. These studies have poised the study of lens development at the forefront of efforts to understand the connections between development, cell signaling, gene transcription and chromatin remodeling.

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“…12), perturbed HS synthesis results in the generation of FGF-related phenotypes (13,14). The crucial role of HS in morphogen transport and on receiving cells has also been demonstrated for vertebrate HH (15)(16)(17)(18) and PDGF function during embryonic vascularization (19).…”

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confidence: 92%

Altered Heparan Sulfate Structure in Mice with Deleted NDST3 Gene Function

Pallerla¹,

Lawrence

Lewejohann

et al. 2008

Journal of Biological Chemistry

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We report the generation and analysis of mutant mice bearing a targeted disruption of the heparan sulfate (HS)-modifying enzyme GlcNAc N-deacetylase/N-sulfotransferase 3 (NDST3). NDST3؊/؊ mice develop normally, are fertile, and show only subtle hematological and behavioral abnormalities in agreement with only moderate HS undersulfation. Compound mutant mice made deficient in NDST2;NDST3 activities also develop normally, showing that both isoforms are not essential for development. In contrast, NDST1؊/؊ ;NDST3 ؊/؊ compound mutant embryos display developmental defects caused by severe HS undersulfation, demonstrating NDST3 contribution to HS synthesis in the absence of NDST1. Moreover, analysis of HS composition in dissected NDST3 mutant adult brain revealed regional changes in HS sulfation, indicating restricted NDST3 activity on nascent HS in defined wild-type tissues. Taken together, we show that NDST3 function is not essential for development or adult homeostasis despite contributing to HS synthesis in a region-specific manner and that the loss of NDST3 function is compensated for by the other NDST isoforms to a varying degree. Heparan sulfate (HS)2 is produced by most mammalian cells as part of membrane and extracellular matrix proteoglycans (1). The chain grows by the copolymerization of GlcA␤1,4 and GlcNAc␣1,4 residues and undergoes modification by one or more of the four NDST isozymes, which remove acetyl groups from subsets of GlcNAc residues and add sulfate to the free amino groups. In vertebrates, ndst1 and ndst2 mRNA are expressed in all embryonic and adult tissues examined, whereas ndst3 and ndst4 transcripts are predominantly expressed during embryonic development and in the adult brain (2). Most subsequent modifications of the HS chain by O-sulfotransferases and a GlcA C5-epimerase depend on the presence of GlcNS residues, making the NDSTs largely responsible for the generation of sulfated ligand binding sites in HS (3-5). In vitro, NDST3 differs biochemically from the other NDST isoforms by possessing a high deacetylase activity but very low sulfotransferase activity (2).Many growth factors and morphogens bind to HS. In some cases, HS-proteoglycans are thought to act as co-receptors for these ligands. Studies in Drosophila melanogaster demonstrated that HS is crucial for embryonic development (6) and that the fly NDST ortholog, Sulfateless, affects signaling mediated by Wingless (Wg), Hedgehog (HH), and fibroblast growth factor (FGF) (7-9). The ability of HS to regulate the activity of morphogens and growth factors is currently best understood for the FGFs. HS was found to be a necessary component of FGF-FGF receptor binding and assembly (10), and global changes in HS expression regulate FGF and FGF receptor assembly during mouse development (11). Due to the multiple developmental processes regulated by the 23 FGFs, including those of the lung, limbs, heart, skeleton, and brain (reviewed in Ref. 12), perturbed HS synthesis results in the generation of FGF-related phenotypes (13,14). The crucial rol...

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

Cited by 54 publications

References 42 publications

Sulfotransferase Ndst1 is Needed for Mandibular and TMJ Development

Sulfotransferase Ndst1 is Needed for Mandibular and TMJ Development

Genetic and epigenetic mechanisms of gene regulation during lens development

Altered Heparan Sulfate Structure in Mice with Deleted NDST3 Gene Function

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