Spatiotemporal expression analysis of the growth factor receptor SorCS3

Abstract

SorCS3 is a member of the Vps10p-D receptor family. These type I transmembrane proteins are regarded as sorting receptors, and some family members modulate signal transduction pathways by acting as co-receptors. SorCS3 binds the nerve growth factor (NGF) and platelet-derived growth factor (PDGF-BB), but the functional implications of these interactions are poorly understood. Here we demonstrate that SorCS3 is almost exclusively expressed in the nervous system and is localized to vesicular structures. By using in situ hybridization, we analyze SorCS3 dynamic expression during embryonic and postnatal development and compare the expression pattern with those of the homologous genes SorCS1 and SorCS2. SorCS3 transcripts are widely distributed in the nervous system but are absent from the embryonic cerebral cortex. SorCS3 expression marks thalamic nuclei at embryonic and early postnatal stages. However, during postnatal development and in the adult, a switch in the localization of SorCS3 transcripts was observed. At these stages forebrain structures, such as the hippocampus and the cerebral cortex, show most prominent expression. The developmental expression pattern of SorCS3 is in accordance with the proposed function as a receptor for growth factors or morphogenic signals. On the cellular level, we demonstrate that the SorCS3 cytoplasmic domain targets receptors to the Golgi apparatus, vesicular structures, and the cell surface. In neurons, receptors are localized to vesicles in the soma and dendrites. Moreover, we show that the SorCS3 cytoplasmic domain conveys internalization through canonical endocytic motifs in an adaptor protein 2 (AP-2)-dependent way. This is in agreement with a proposed function as a neuronal sorting receptor.

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

“…These neurons express SorCS2 and SorCS3, but express SorCS1 at very low levels or not at all (Hermey et al, 2004; Oetjen et al, 2014). We tested multiple Nrxn antibodies, but none of these proved suitable for the detection of endogenous cell surface Nrxn (data not shown).…”

“…We next tested the effect of loss of SorCS1 on dendritic Nrxn surface levels. We cultured cortical neurons, which strongly express SorCS1 (Hermey et al, 2004; Oetjen et al, 2014), from SorCS1 flox/flox mice (Lane et al, 2010) and expressed Cre recombinase in these cells to reduce SorCS1 levels. Compared to control cells, the surface SEP-Nrxn1β ratio was significantly increased in SorCS1 KO dendrites (Fig.…”

“…Less is known about the sorting function and endogenous cargo of the three remaining mammalian VPS10P receptors, SorCS (sortilin-related CNS expressed) 1, -2, and -3 (Hermey et al, 2004; Hermey et al, 1999; Rezgaoui et al, 2001). The three SorCS genes are expressed in complementary patterns in the brain (Hermey et al, 2004; Oetjen et al, 2014), SorCS3 localizes to synapses (Breiderhoff et al, 2013), and SORCS genes have been associated with autism, schizophrenia, bipolar disorder, ADHD, and late-onset Alzheimer's disease (Christoforou et al, 2011; Grupe et al, 2006; Laumet et al, 2010; Li et al, 2008; Liang et al, 2009; Lionel et al, 2011; Ollila et al, 2009; Reitz et al, 2011; Sanders et al, 2012). Their prominent association with synaptopathies suggests that SorCS receptors might play a role in the trafficking of synaptic components.…”

Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo

“…In situ hybridization was essentially performed as described before59. In brief, antisense RNA probes labelled with [α- 35 S]-UTP were generated according to the manufacturer’s instructions (Promega).…”

Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear

“…Transcripts of SorCS2 have been detected in cochlear tissue at E18 [41] and it is shown here that in normal animals not only is the gene expressed in the inner ear postnatally but also it is translated into protein in the organ of Corti, vestibular maculae and cristae from embryonic ages, when hair cells are first formed, through to the mature tissues. Its expression was severely reduced or absent from the inner ears of animals which exhibited anomalous bundles.…”