Sortilin regulates sorting and secretion of Sonic hedgehog

Campbell, Charles Macfie; Beug, Shawn T.; Nickerson, Philip E.B.; Peng, Jimmy; Mazerolle, Chantal; Bassett, Erin A.; Ringuette, Randy; Jama, Fadumo A; Morales, Carlos R.; Christ, Annabel; Wallace, Valerie A.

doi:10.1242/jcs.183541

Cited by 16 publications

(11 citation statements)

References 72 publications

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“…1C). HhU self-cleavage to yield HhNp and HhC 24 is thought to occur in the ER (Campbell et al, 2016; Chen et al, 2011). To determine how HhC 24 and HhC 16 are processed, we employed Hh-expressing cell lines which enabled us to observe the generation and degradation order of Hh products, the secretion of each fragment, and the organellar compartments in which these events occur.…”

Section: Resultsmentioning

confidence: 99%

A novel proteolytic event controls Hedgehog intracellular sorting and distribution to receptive fields

2017

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The patterning activity of a morphogen depends on secretion and dispersal mechanisms that shape its distribution to the cells of a receptive field. In the case of the protein Hedgehog (Hh), these mechanisms of secretion and transmission remain unclear. In the developing Drosophila visual system, Hh is partitioned for release at opposite poles of photoreceptor neurons. Release into the retina regulates the progression of eye development; axon transport and release at axon termini trigger the development of postsynaptic neurons in the brain. Here we show that this binary targeting decision is controlled by a C-terminal proteolysis. Hh with an intact C-terminus undergoes axonal transport, whereas a C-terminal proteolysis enables Hh to remain in the retina, creating a balance between eye and brain development. Thus, we define a novel mechanism for the apical/basal targeting of this developmentally important protein and posit that similar post-translational regulation could underlie the polarity of related ligands.

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Section: Resultsmentioning

confidence: 99%

A novel proteolytic event controls Hedgehog intracellular sorting and distribution to receptive fields

2017

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“…In addition to the effect of sortilin on NT function, reports have established that sortilin interacts with other known molecules of relevance for neural development. Most notably, a recent report found that sortilin is a regulator of sonic hedgehog secretion, a protein with profound impact on CNS patterning and development (Campbell et al, ). Sortilin enhances signaling of ciliary neurotrophic factor (CNTF), shown to mediate survival of several neuronal subtypes (Larsen et al, ; Sango, Yanagisawa, Komuta, Si, & Kawano, ) and decreases levels of progranulin, a protein involved in the pathogenesis of frontotemporal lobar dementia (Baker et al, ; Hu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Highly segregated localization of the functionally related vps10p receptors sortilin and SorCS2 during neurodevelopment

Boggild

Mølgaard

Glerup

et al. 2018

J of Comparative Neurology

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Nervous system development is a precisely orchestrated series of events requiring a multitude of intrinsic and extrinsic cues. Sortilin and SorCS2 are members of the Vps10p receptor family with complementary influence on some of these cues including the neurotrophins (NTs). However, the developmental time points where sortilin and SorCS2 exert their activities in conjunction or independently still remain unclear. In this study we present the characterization of the spatiotemporal expression pattern of sortilin and SorCS2 in the developing murine nervous system. Sortilin is highly expressed in the fetal nervous system with expression localized to distinct cell populations. Expression was high in neurons of the cortical plate and developing allocortex, as well as subpallial structures. Furthermore, the neuroepithelium lining the ventricles and the choroid plexus showed high expression of sortilin, together with the developing retina, spinal ganglia, and sympathetic ganglia. In contrast, SorCS2 was confined in a marked degree to the thalamus and, at E13.5, the floor plate from midbrain rostrally to spinal cord caudally. SorCS2 was also found in the ventricular zones of the ventral hippocampus and nucleus accumbens areas, in the meninges and in Schwann cells. Hence, sortilin and SorCS2 are extensively present in several distinct anatomical areas in the developing nervous system and are rarely co-expressed. Possible functions of sortilin and SorCS2 pertain to NT signaling, axon guidance and beyond. The present data will form the basis for hypotheses and study designs for unravelling the functions of sortilin and SorCS2 during the establishment of neuronal structures and connections.

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“…The association of Ihh with the apical brush border of principal cells strongly suggests that IHH ligand can be released into the extracellular space, possibility through the activity of protein dispatched homologs ( DISP1 and/or DISP2) whose function consists in regulating the effective release of membrane‐bound cholesterol‐modified Hh ligands 40 . Furthermore, the co‐localization of Ihh with the trans‐Golgi system may suggests the existence of a retention process of IHH in the Golgi system to modulate its secretion, as it has been described for SHH 41 …”

Section: Discussionmentioning

confidence: 88%

Hedgehog signaling pathway regulates gene expression profile of epididymal principal cells through the primary cilium

et al. 2020

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Primary cilia (PC) are organelles that sense and respond to dynamic changes of the extracellular milieu through the regulation of target genes. By using the epididymis as a model system, we determined the contribution of primary cilia in the regulation of epithelial cell functions through the transduction of the Hedgehog (Hh) signaling pathway. Both Sonic (SHH) and Indian Hedgehog (IHH) ligands were detected in epididymal epithelial cells by confocal microscopy and found secreted in the extracellular space. Gene expression profiling preformed on ciliated epithelial cells indicated that 153 and 1052 genes were differentially expressed following treatment with the Hh agonist SAG or the Hh antagonist cyclopamine (Cyclo), respectively. Strikingly, gene ontology analysis indicated that genes associated with immune response were the most affected following Hh modulation. The contribution of epididymal PC to canonical Hh pathway transduction was validated by ciliobrevin D treatment, which induced a significant decrease in PC length and a reduction in the expression Hh signaling targets. Such findings bring us closer to a molecular understanding of the subtle immune balance observed in some epithelia, including the epididymis and the intestine, which are organs featuring both tolerance toward autoimmune spermatozoa (or commensal bacteria) and defense against pathogens.

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Sortilin regulates sorting and secretion of Sonic hedgehog

Cited by 16 publications

References 72 publications

A novel proteolytic event controls Hedgehog intracellular sorting and distribution to receptive fields

A novel proteolytic event controls Hedgehog intracellular sorting and distribution to receptive fields

Highly segregated localization of the functionally related vps10p receptors sortilin and SorCS2 during neurodevelopment

Hedgehog signaling pathway regulates gene expression profile of epididymal principal cells through the primary cilium

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