<scp>GDE2</scp> expression in oligodendroglia regulates the pace of oligodendrocyte maturation

Choi, Bo Ran; Dobrowolski, Mateusz; Sockanathan, Shanthini

doi:10.1002/dvdy.265

Cited by 7 publications

(6 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 K, L ). Similar to previous studies using younger mice [ 31 , 32 ], Gde2 expression in the cortex is mainly localized to neurons with some expression in non-neuronal cells (Fig. 1 M, N ).…”

Section: Resultssupporting

confidence: 89%

See 1 more Smart Citation

Loss of GDE2 leads to complex behavioral changes including memory impairment

Daudelin,

Westerhaus,

Zhang

et al. 2024

Behav Brain Funct

Self Cite

View full text Add to dashboard Cite

Background Alzheimer’s disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized. Results Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition. Conclusions Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.

show abstract

Section: Resultssupporting

confidence: 89%

“…GDE2 is expressed in the developing and postnatal spinal cord and brain [ 20 , 31 , 32 ]; however, its expression in the adult brain has not been determined. To assess GDE2 expression in the adult mouse brain, we performed RNAscope for Gde2 transcripts in coronal sections from 4-month-old WT mice.…”

Section: Resultsmentioning

confidence: 99%

Loss of GDE2 leads to complex behavioral changes including memory impairment

Daudelin,

Westerhaus,

Zhang

et al. 2024

Behav Brain Funct

Self Cite

View full text Add to dashboard Cite

show abstract

“…These vesicular GPI-anchored proteins retain the lipid tail and are associated with membrane structure. We tested for the possibility that GPC4 is released through an extra vesicular fraction like some GPI anchored proteins such as CNTFR ( Choi et al, 2021 ). In this model of release, GPI-anchored GPC4 is expressed on the cell surface, and released while still bound to the membranes of extracellular vesicles either through exosomal or ectosomal pathways.…”

Section: Resultsmentioning

confidence: 99%

Heparan Sulfated Glypican-4 Is Released from Astrocytes by Proteolytic Shedding and GPI-Anchor Cleavage Mechanisms

Huang

Park

2021

eNeuro

View full text Add to dashboard Cite

Astrocytes provide neurons with diffusible factors that promote synapse formation and maturation. In particular, glypican-4/GPC4 released from astrocytes promotes the maturation of excitatory synapses. Unlike other secreted factors, GPC4 contains the C-terminal GPIanchorage signal. However, the mechanism by which membrane-tethered GPC4 is released from astrocytes is unknown. Using mouse primary astrocyte cultures and a quantitative luciferase-based release assay, we show that GPC4 is expressed on the astrocyte surface via a GPI-anchorage. Soluble GPC4 is robustly released from the astrocytes largely by proteolytic shedding and, to a lesser extent, by GPI-anchor cleavage, but not by vesicular release. Pharmacological, overexpression, and loss of function screens showed that ADAM9 in part mediates the release of GPC4 from astrocytes. The released GPC4 contains the heparan sulfate side chain, suggesting that these release mechanisms provide the active form that promotes synapse maturation and function. Overall, our studies identified the release mechanisms and the major releasing enzyme of GPC4 in astrocytes and will provide insights into understanding how astrocytes regulate synapse formation and maturation. Significance StatementAstrocyte-derived diffusible factors regulate synapse development and function. However, the regulatory mechanism underlying the release of astrocyte-derived factors is poorly understood.Noting that, unlike many other secreted factors, glypican-4/GPC4 is GPI-anchored, we characterized the release mechanism of GPI-anchored GPC4 from astrocytes and identified the releasing enzyme. Heparan sulfated GPC4 is robustly released from the astrocytes largely by proteolytic shedding. In particular, ADAM9 in part mediates the release of GPC4 from astrocytes. Our study provides an enzymatic mechanism for releasing GPC4 from astrocytes and will provide a novel opportunity to understand the regulatory mechanism of neuron-glia communication for synaptogenesis.

show abstract

“…The two other six-transmembrane GDE proteins (GDE2 and GDE3) have mutually exclusive expression patterns, with GDE2 expression in neurons and oligodendrocytes and GDE3 expression in oligodendrocyte precursor cells (OPCs) and astrocytes ( Choi et al, 2020b ; Dobrowolski et al, 2020 ). GDE6 is unique as it is the first of the six-transmembrane GDE proteins expressed in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past decade, family members of the six-transmembrane Glycerophosphodiester Phosphodiesterases (GDEs) have been identified as integral molecules in the context of cell proliferation and differentiation during neurodevelopment ( Rao and Sockanathan, 2005 ; Yan et al, 2009 ; Sabharwal et al, 2011 ; Rodriguez et al, 2012 ; Choi et al, 2020b ). These proteins share a six-transmembrane topology with intracellular N- and C-termini and an extracellular enzymatic (GDPD) domain.…”

Section: Introductionmentioning

confidence: 99%

GDE6 promotes progenitor identity in the vertebrate neural tube

et al. 2023

View full text Add to dashboard Cite

The generation of neurons in the central nervous system is a complex, stepwise process necessitating the coordinated activity of mitotic progenitors known as radial glia. Following neural tube closure, radial glia undergo a period of active proliferation to rapidly expand their population, creating a densely packed neurepithelium. Simultaneously, radial glia positioned across the neural tube are uniquely specified to produce diverse neuronal sub-types. Although these cellular dynamics are well studied, the molecular mechanisms governing them are poorly understood. The six-transmembrane Glycerophosphodiester Phosphodiesterase proteins (GDE2, GDE3, and GDE6) comprise a family of cell-surface enzymes expressed in the embryonic nervous system. GDE proteins can release Glycosylphosphatidylinositol-anchored proteins from the cell surface via cleavage of their lipid anchor. GDE2 has established roles in motor neuron differentiation and oligodendrocyte maturation, and GDE3 regulates oligodendrocyte precursor cell proliferation. Here, we describe a role for GDE6 in early neural tube development. Using RNAscope, we show that Gde6 mRNA is expressed by ventricular zone progenitors in the caudal neural tube. Utilizing in-ovo electroporation, we show that GDE6 overexpression promotes neural tube hyperplasia and ectopic growths of the neurepithelium. At later stages, electroporated embryos exhibit an expansion of the ventral patterning domains accompanied by reduced cross-repression. Ultimately, electroporated embryos fail to produce the full complement of post-mitotic motor neurons. Our findings indicate that GDE6 overexpression significantly affects radial glia function and positions GDE6 as a complementary factor to GDE2 during neurogenesis.

show abstract

GDE2 expression in oligodendroglia regulates the pace of oligodendrocyte maturation

Cited by 7 publications

References 54 publications

Loss of GDE2 leads to complex behavioral changes including memory impairment

Loss of GDE2 leads to complex behavioral changes including memory impairment

Heparan Sulfated Glypican-4 Is Released from Astrocytes by Proteolytic Shedding and GPI-Anchor Cleavage Mechanisms

GDE6 promotes progenitor identity in the vertebrate neural tube

Contact Info

Product

Resources

About