TABLE 1.
Summary of apoER2 alternatively spliced exons, including their associated in vitro and in vivo phenotypes, spatiotemporal distribution and known splicing regulators.
| Alternative Exon | Functional domain affected | In vitro phenotype | In vivo phenotype | Spatiotemporal distribution | Splicing regulator | Associated publications |
| Murine and Human exon 5 | LDLa ligand binding repeats 4–6 | Required for α2-macroglobulin binding (HEK-293 cells) | Unknown |
Murine: – solely Δex5 detected (total brain RNA) Human: – +/Δex5 detected (total brain RNA) – solely Δex5 detected in adult frontal cortex, hippocampus and cerebellum and fetal brain (RNA) |
Unknown | Kim et al., 1997; Clatworthy et al., 1999; Brandes et al., 2001 |
| Murine exon 7 | LDLa ligand binding repeat 8 (lacking in humans) | – Exclusion leads to lower affinity for β-VLDL particles (HEK-293 cells) – Exclusion confers altered affinity for reelin cleavage products (COS7 cells) |
Unknown | – +/Δex7 both detected (total brain RNA) – Δex7 only at E10 (total brain RNA) – +/Δex7 at E12 and E15/16 (total brain RNA) – E15/16: cerebrum contains +/Δex7 while cerebellum and olfactory bulbs soley express +ex7 (RNA) – Ex7 cerebrum expression higher at E15-17 than P10 (protein) – Ex7 cerebellar expression increases from E17 to P10 (protein) – Cerebellum contains higher ex7 levels than cerebrum at P10 (protein) – P10 cerebellum: ex7 expression in internal granule cell layer but not external granule layer or Purkinje cells (protein) – E17 ex7 expression in cortical plate, but scarce in Marginal, Intermediate and Subventricular zones (protein) |
Unknown | Brandes et al., 1997, 2001; Kim et al., 1998; Koch et al., 2002; Hibi et al., 2009 |
| Murine exon 7B (Human exon 6B) |
Furin cleavage site | – Cleaved in furin dependent manner (HEK-293 cells) – Extracellular cleavage product binds reelin – Cleavage product suppresses Dab1 phosphorylation (primary neurons IP) |
Cleavage product remains undetected in brain |
Murine: – low level inclusion of ex7B (total adult and embryonic brain RNA) – mutually exclusive with ex7 (total brain RNA) – low level inclusion of ex7B in E15-16 cerebrum but none in E15-16 cerebellum or olfactory bulb (RNA) Human: – low level inclusion of ex6B (total brain RNA) |
Preliminary evidence for Rbfox2 | Brandes et al., 1997, 2001; Koch et al., 2002; Gehman et al., 2012 |
| Murine exon 16 (Human exon 15) |
O-linked glycosylation site; extracellular cleavage site | – Required for extracellular cleavage by metalloproteases (HEK-293 cells and primary neurons) – Required for receptor sugar glycosylation (CHO cells and brain lysate) – Exclusion alters hippocampal LTP and CA1 synaptic strength in exon 19 dependent manner (hippocampal slice electrophysiology) |
Murine: Constitutive exclusion leads to: – increased brain apoER2 mRNA and protein levels – increase in hippocampal dendritic spines – impaired fear acquisition (context and cued fear conditioning task) – augmented glutamate receptor expression |
Human: – +/Δex15 both detected in adult frontal cortex, hippocampus and cerebellum and fetal brain (RNA) |
Unknown | Clatworthy et al., 1999; Wasser et al., 2014 |
| Murine exon 19 (Human exon 18) |
Cytoplasmic insert | – Binds adaptor proteins JIP1, JIP2, PSD-95, APBA1, APBA2 (Y2H screen, IP) – Required for reelin-induced LTP in hippocampus (hippocampal slice electrophysiology) |
Murine: Ex19 inclusion lower in aging and amyloid mouse model hippocampus (semi-qRT-PCR) Constitutive exclusion confers: – deficits in hippocampal dependent learning (fear conditioning/associative learning) – decreased number of adult corticospinal neurons – decreased thickness of adult primary motor cortex – protection from corticospinal neuronal death following brain injury Human: – Ex18 inclusion is lower in middle temporal region of the AD brain (semi-qRT-PCR) – Ex18 inclusion associated with global cognition (linear regression models) |
Murine: – brain stem cells solely express Δex19 – approximately equal +/Δex19 levels found in primary neurons, total brain RNA and hippocampal RNA – ex19 confirmed at protein level (total brain lysate) Human: – approximately equal +/Δex18 levels in adult middle temporal region, frontal cortex, hippocampus and cerebellum and whole fetal and adult brains (RNA) |
– Moderate evidence for SRSF1 – Activity regulated |
Kim et al., 1998; Clatworthy et al., 1999; Stockinger et al., 2000; Gotthardt et al., 2000; Beffert et al., 2005; Beffert et al., 2006; He et al., 2007; Hinrich et al., 2016 |
LDLa, Low density lipoprotein receptor class A; HEK-293, Human Embryonic Kidney-293; VLDL, Very low density lipoprotein; IP, immunoprecipitation; LTP, Long term potentiation; Y2H, Yeast-2-Hybrid; qRT-PCR, quantitative real time-polymerase chain reaction.