GDE2 Regulates Subtype-Specific Motor Neuron Generation through Inhibition of Notch Signaling

Sabharwal, Priyanka; Lee, ChangHee; Park, Sung Jin; Rao, Meenakshi; Sockanathan, Shanthini

doi:10.1016/j.neuron.2011.07.028

Cited by 46 publications

(72 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gde2 protein expression was analyzed in WT mice using polyclonal antibodies directed against the C-terminal portion of the protein and specificity was confirmed by loss of antibody reactivity in Gde2 -/-littermates ( Fig. 1AЈ-CЈ,AЉ-CЉ) (Sabharwal et al, 2011). Gde2 protein showed a similar temporal and spatial distribution pattern to Gde2 transcripts with enrichment of Gde2 in postmitotic neurons ( Fig.…”

Section: Gde2 Is Expressed In the Developing Cortexmentioning

confidence: 79%

“…One such pathway has been described in the developing spinal cord. Here, the sixtransmembrane protein Gde2 (Gdpd5 -Mouse Genome Informatics) regulates the timing of motor neuron progenitor differentiation and the generation of different motor neuron subtypes through the downregulation of Notch signaling (Rao and Sockanathan, 2005;Nogusa et al, 2004;Yan et al, 2009;Sabharwal et al, 2011). Gde2 is expressed in early-born medial motor column (MMC) motor neurons, where it acts non-cellautonomously to inhibit Notch signaling in adjacent motor neuron progenitors using extracellular glycerophosphodiester phosphodiesterase (GDPD) activity (Sabharwal et al, 2011).…”

Section: Abstract: Gde2 Cortex Differentiation Mousementioning

confidence: 99%

“…Here, the sixtransmembrane protein Gde2 (Gdpd5 -Mouse Genome Informatics) regulates the timing of motor neuron progenitor differentiation and the generation of different motor neuron subtypes through the downregulation of Notch signaling (Rao and Sockanathan, 2005;Nogusa et al, 2004;Yan et al, 2009;Sabharwal et al, 2011). Gde2 is expressed in early-born medial motor column (MMC) motor neurons, where it acts non-cellautonomously to inhibit Notch signaling in adjacent motor neuron progenitors using extracellular glycerophosphodiester phosphodiesterase (GDPD) activity (Sabharwal et al, 2011). Genetic ablation of Gde2 results in deficits in alpha motoneurons of the limb-innervating lateral motor column (LMC); namely, early-born LMC motor pool formation is delayed and late-born LMC motor pools fail to differentiate (Sabharwal et al, 2011;Kanning et al, 2010).…”

Section: Abstract: Gde2 Cortex Differentiation Mousementioning

confidence: 99%

“…Gde2 is expressed in early-born medial motor column (MMC) motor neurons, where it acts non-cellautonomously to inhibit Notch signaling in adjacent motor neuron progenitors using extracellular glycerophosphodiester phosphodiesterase (GDPD) activity (Sabharwal et al, 2011). Genetic ablation of Gde2 results in deficits in alpha motoneurons of the limb-innervating lateral motor column (LMC); namely, early-born LMC motor pool formation is delayed and late-born LMC motor pools fail to differentiate (Sabharwal et al, 2011;Kanning et al, 2010). Based on these observations, we investigated the possibility that Gde2 constitutes a regulatory mechanism that plays important roles in other systems where the timing of neurogenesis is a key factor in controlling neuronal fate and numbers, such as the developing cortex.…”

Section: Abstract: Gde2 Cortex Differentiation Mousementioning

confidence: 99%

“…Generation of Gde2 -/-and Gde2 lox mice and genotyping was performed as described previously (Sabharwal et al, 2011). All animal procedures were carried out according to Johns Hopkins University IACUC guidelines.…”

Section: Animals and Genotypingmentioning

confidence: 99%

See 4 more Smart Citations

Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation

et al. 2012

Self Cite

View full text Add to dashboard Cite

The mammalian cortex is a multilaminar structure consisting of specialized layer-specific neurons that form complex circuits throughout the brain and spinal cord. These neurons are generated in a defined sequence dictated by their birthdate such that early-born neurons settle in deep cortical layers whereas late-born neurons populate more superficial layers. Cortical neuronal birthdate is partly controlled by an intrinsic clock-type mechanism; however, the role of extrinsic factors in the temporal control of cell-cycle exit is less clear. Here, we show that Gde2, a six-transmembrane protein that induces spinal neuronal differentiation, is expressed in the developing cortex throughout cortical neurogenesis. In the absence of Gde2, cortical progenitors fail to exit the cell cycle on time, remain cycling, accumulate and exit the cell cycle en masse towards the end of the neurogenic period. These dynamic changes in cell-cycle progression cause deficits and delays in deep-layer neuronal differentiation and robust increases in superficial neuronal numbers. Gde2−/− cortices show elevated levels of Notch signaling coincident with when progenitors fail to differentiate, suggesting that abnormal Notch activation retains cells in a proliferative phase that biases them to superficial fates. However, no change in Notch signaling is observed at the time of increased cell-cycle exit. These observations define a key role for Gde2 in controlling cortical neuronal fates by regulating the timing of neurogenesis, and show that loss of Gde2 uncovers additional mechanisms that trigger remaining neuronal progenitors to differentiate at the end of the neurogenic period.

show abstract

Section: Gde2 Is Expressed In the Developing Cortexmentioning

confidence: 79%

Section: Abstract: Gde2 Cortex Differentiation Mousementioning

confidence: 99%

Section: Abstract: Gde2 Cortex Differentiation Mousementioning

confidence: 99%

Section: Abstract: Gde2 Cortex Differentiation Mousementioning

confidence: 99%

Section: Animals and Genotypingmentioning

confidence: 99%

See 3 more Smart Citations

Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

Regulation of Neuronal Subtype Identity in the Vertebrate Neural Tube (Neuronal Subtype Identity Regulation)

Bushati¹,

Briscoe²

2012

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

The vertebrate nervous system consists of many different neuronal cell types. Each has its own properties, axon projections and connection patterns. This diversity is established early during development and is required for the complex neuronal circuits that characterise the central nervous system. In the spinal cord, a series of events generates different neuronal subtypes, starting with the spatial patterning of neural progenitors. Extrinsic signals provide progenitors in the forming neural tube with positional identity, such that distinct types of progenitors express a unique combination of transcription factors. This transcriptional code determines neural progenitor identity. As progenitors differentiate, they generate distinct neuronal subtypes that are also characterised by a combinatorial transcriptional code. In addition to spatial patterning, other mechanisms contribute to the further diversification of differentiating neurons. Key Concepts: Secreted molecules provide positional information to neural progenitors in the developing neural tube. Progenitors at different positions in the neural tube acquire distinct identities. The identity of a progenitor is defined by the combination of transcription factors it expresses, which determines the gene expression profile of the progenitor. An interplay between extrinsic signalling and the downstream gene network produces spatially discrete switches in progenitor identity. Progenitors with distinct identities differentiate into post‐mitotic neurons with different subtype identities. The identity of a neuron is determined by the transcriptional code of its progenitor and is itself defined by a separate transcriptional code. In addition to spatial pattern, temporal changes in progenitor identity and signalling between differentiating cells increases neuronal diversity.

show abstract

GDE2 expression in oligodendroglia regulates the pace of oligodendrocyte maturation

Choi

Dobrowolski

Sockanathan

2020

Developmental Dynamics

Self Cite

View full text Add to dashboard Cite

Background: Oligodendrocytes generate specialized lipid-rich sheaths called myelin that wrap axons and facilitate the rapid, saltatory transmission of action potentials. Extrinsic signals and surface-mediated pathways coordinate oligodendrocyte development to ensure appropriate axonal myelination, but the mechanisms involved are not fully understood. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane enzyme that regulates the activity of surface glycosylphosphatidylinositol (GPI)-anchored proteins by cleavage of the GPI-anchor. GDE2 is expressed in neurons where it promotes oligodendrocyte maturation through the release of neuronallyderived soluble factors. GDE2 is also expressed in oligodendrocytes but the function of oligodendroglial GDE2 is not known. Results: Using Cre-lox technology, we generated mice that lack GDE2 expression in oligodendrocytes (O-Gde2KO). O-Gde2KOs show normal production and proliferation of oligodendrocyte precursor cells. However, oligodendrocyte maturation is accelerated leading to the robust increase of myelin proteins and increased myelination during development. These in vivo observations are recapitulated in vitro using purified primary oligodendrocytes, supporting cellautonomous functions for GDE2 in oligodendrocyte maturation. Conclusions: These studies reveal that oligodendroglial GDE2 expression is required for controlling the pace of oligodendrocyte maturation. Thus, the celltype specific expression of GDE2 is important for the coordination of oligodendrocyte maturation and axonal myelination during neural development.

show abstract

GDE2 Regulates Subtype-Specific Motor Neuron Generation through Inhibition of Notch Signaling

Cited by 46 publications

References 52 publications

Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation

Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation

Regulation of Neuronal Subtype Identity in the Vertebrate Neural Tube (Neuronal Subtype Identity Regulation)

GDE2 expression in oligodendroglia regulates the pace of oligodendrocyte maturation

Contact Info

Product

Resources

About