Lipoprotein-Heparan Sulfate Interactions in the Hh Pathway

Eugster, Christina; Panàkovà, Daniela; Mahmoud, Ali; Eaton, Suzanne

doi:10.1016/j.devcel.2007.04.019

Cited by 149 publications

(177 citation statements)

References 51 publications

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“…Movement of Hh proteins in the extracellular space is limited by covalent lipid modifications at both aminoand carboxyl-terminal domains (38,39). Lipid-modified Hh proteins are secreted as multimers that interact with heparan sulfate proteoglycans (HSPGs), which further restricts their movement (40,41). Our data suggest that Shh protein is concentrated between the media and adventitia because of local synthesis, secretion, and retention of Shh multimers by ECM components, such as the HSPG perlecan (42), in the artery wall.…”

Section: Discussionmentioning

confidence: 99%

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells

Passman

Dong²,

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

272

342

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We characterize a sonic hedgehog (Shh) signaling domain restricted to the adventitial layer of artery wall that supports resident Sca1-positive vascular progenitor cells (AdvSca1). Using patched-1 (Ptc1 lacZ ) and patched-2 (Ptc2 lacZ ) reporter mice, adventitial Shh signaling activity was first detected at embryonic day (E) 15.5, reached the highest levels between postnatal day 1 (P1) and P10, was diminished in adult vessels, and colocalized with a circumferential ring of Shh protein deposited between the media and adventitia. In Shh ؊/؊ mice, AdvSca1 cells normally found at the aortic root were either absent or greatly diminished in number. Using a Wnt1-cre lineage marker that identifies cells of neural crest origin, we found that neither the adventitia nor AdvSca1 cells were labeled in arteries composed of neural crest-derived smooth muscle cells (SMCs). Although AdvSca1 cells do not express SMC marker proteins in vivo, they do express transcription factors thought to be required for SMC differentiation, including serum response factor (SRF) and myocardin family members, and readily differentiate to SMC-like cells in vitro. However, AdvSca1 cells also express potent repressors of SRF-dependent transcription, including Klf4, Msx1, and FoxO4, which may be critical for maintenance of the SMC progenitor phenotype of AdvSca1 cells in vivo. We conclude that a restricted domain of Shh signaling is localized to the arterial adventitia and may play important roles in maintenance of resident vascular SMC progenitor cells in the artery wall.artery ͉ differentiation ͉ Klf4 ͉ self-renewal ͉ serum response factor

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Section: Discussionmentioning

confidence: 99%

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells

Passman

Dong²,

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

272

342

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“…Thus, an enhanced interaction with glypican-3 would further reduce the signaling capacity via PTC1. Studies have suggested that HSPGs can facilitate Hh movement by means of lipoprotein binding in the extracellular matrix and can antagonize PTC-mediated Hh sequestration, thereby promoting long-range movement [41,42]. Furthermore, a recent study has shown that Hh monomers can form nanoscale oligomers that are selectively enriched in visible clusters containing HSPGs [43].…”

Section: Discussionmentioning

confidence: 99%

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Xiao

et al. 2011

Cell Res

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Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.

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“…We previously reported that lipid-linked proteins (including GPIlinked, cholesterol-modified and palmitoylated proteins) associate with Lpp, permitting their local mobilization (Panáková et al, 2005;Eugster et al, 2007 (Fig. 4 A).…”

Section: Apol-tevmentioning

confidence: 92%

“…Antibodies were diluted as follows: anti-HA16B12 1:1500 (Santa Cruz Biotechnology), anti-Elav7E8A10 1:1500 [Developmental Studies Hybridoma Bank (DSHB), University of Iowa, Iowa City, IA], anti-HRPCy5 1:500 (Dianova), anti-Lpp (Eugster et al, 2007) (Wang and Holmgren, 1999), anti-Dpn (1:30) (Boone and Doe, 2008), anti-Myc 1:1000 (Gramsch), anti-Prospero-MR1A 1:750 (DSHB), anti-Repo8D12 1:500 (DSHB) and anti-phosphohistone H3 6G3 1:1500 (Cell Signaling Technology). Phalloidin-Cy5 1:200 (Invitrogen) and FilipinIII 1:500 (Sigma).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

Brankatschk

Eaton

2010

J. Neurosci.

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The blood-brain barrier (BBB) regulates passage of nutrients and signaling molecules from the circulation into the brain. Whether lipoproteins cross the BBB in vivo has been controversial, and no clear requirement for circulating lipoproteins in brain development has been shown. We address these issues in Drosophila, which has an functionally conserved BBB, and lipoproteins that resemble those of vertebrates. We show that the Drosophila lipoprotein lipophorin exists in two isoforms. Both isoforms cross the BBB, but accumulate on distinct subsets of cells within the brain. In addition to acting as a lipid carrier, lipophorin carries both sterol-linked and GPI-linked proteins into the circulation and transports them across the BBB. Finally, lipophorin promotes neuroblast proliferation by a mechanism that does not depend on delivery of dietary lipids. Transport of lipophorin and its cargo across the BBB represents a novel mechanism by which peripherally synthesized proteins might enter the brain and influence its development. Furthermore, lipid-linkage may be an efficient method to transport therapeutic molecules across the BBB.

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Lipoprotein-Heparan Sulfate Interactions in the Hh Pathway

Cited by 149 publications

References 51 publications

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

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Lipoprotein-Heparan Sulfate Interactions in the Hh Pathway

Cited by 149 publications

References 51 publications

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 + smooth muscle progenitor cells

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 + smooth muscle progenitor cells

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

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Product

Resources

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A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells

A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1 ⁺ smooth muscle progenitor cells