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/dev.145870

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…1 C). 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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“…Thus, it is possible that impaired phosphorylation of Y1062 in c-Ret causes impairments of neurite outgrowth and SV2-mediated Shh trafficking in PCs, resulting in hypoplasia of GCs and glial fibers with decreased expression of BLBP. In a previous study, Sortilin, a multifunctional sorting receptor, was shown to regulate Shh trafficking (41). Therefore, it is possible that Shh trafficking is mediated by not only SV2-mediated processes but also other processes.…”

Section: Discussionmentioning

confidence: 98%

Loss-of-function mutation of c-Ret causes cerebellar hypoplasia in mice with Hirschsprung disease and Down's syndrome

Ohgami

Iizuka

Hirai

et al. 2021

Journal of Biological Chemistry

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The c- RET proto-oncogene encodes a receptor-tyrosine kinase. Loss-of-function mutations of RET have been shown to be associated with Hirschsprung disease and Down's syndrome (HSCR-DS) in humans. DS is known to involve cerebellar hypoplasia, which is characterized by reduced cerebellar size. Despite the fact that c-Ret has been shown to be associated with HSCR-DS in humans and to be expressed in Purkinje cells (PCs) in experimental animals, there is limited information about the role of activity of c-Ret/c-RET kinase in cerebellar hypoplasia. We found that a loss-of-function mutation of c-Ret Y1062 in PCs causes cerebellar hypoplasia in c-Ret mutant mice. Wild-type mice had increased phosphorylation of c-Ret in PCs during postnatal development, while c-Ret mutant mice had postnatal hypoplasia of the cerebellum with immature neurite outgrowth in PCs and granule cells (GCs). c-Ret mutant mice also showed decreased numbers of glial fibers and mitogenic sonic hedgehog (Shh)-positive vesicles in the external germinal layer of PCs. c-Ret-mediated cerebellar hypoplasia was rescued by subcutaneous injection of a smoothened agonist (SAG) as well as by reduced expression of Patched1 , a negative regulator for Shh. Our results suggest that the loss-of-function mutation of c-Ret Y1062 results in the development of cerebellar hypoplasia via impairment of the Shh-mediated development of GCs and glial fibers in mice with HSCR-DS.

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Sortilin regulates sorting and secretion of Sonic hedgehog

Cited by 3 publications

References 32 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

Loss-of-function mutation of c-Ret causes cerebellar hypoplasia in mice with Hirschsprung disease and Down's syndrome

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