Developmental role of adenosine kinase in the cerebellum

Hoda Gebril; Amir Wahba; Xiaofeng Zhou; Tho Lai; Enmar Alharfoush; Emanuel Dicicco-Bloom; Detlev Boison

doi:https://doi.org/10.1523/ENEURO.0011-21.2021

Developmental role of adenosine kinase in the cerebellum

Hoda Gebril, Amir Wahba, Xiaofeng Zhou, Tho Lai, Enmar Alharfoush, Emanuel Dicicco-Bloom, Detlev Boison

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner in vitro. In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.

Original language	English (US)
Article number	ENEURO.0011-21.2021
Journal	eNeuro
Volume	8
Issue number	3
DOIs	https://doi.org/10.1523/ENEURO.0011-21.2021
State	Published - 2021

ASJC Scopus subject areas

Neuroscience(all)

Keywords

Adenosine
Adenosine kinase
Cell proliferation
Cerebellum
Development
Granule neuron precursors

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https://doi.org/10.1523/ENEURO.0011-21.2021

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title = "Developmental role of adenosine kinase in the cerebellum",

abstract = "Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner in vitro. In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.",

keywords = "Adenosine, Adenosine kinase, Cell proliferation, Cerebellum, Development, Granule neuron precursors",

author = "Hoda Gebril and Amir Wahba and Xiaofeng Zhou and Tho Lai and Enmar Alharfoush and Emanuel Dicicco-Bloom and Detlev Boison",

note = "Funding Information: This work was supported by Dale & Beverly Rice, National Institutes of Health Grants NS065957 and NS103740 (to D.B.), and Citizens United for Research in Epilepsy (CURE Catalyst Award; D.B.). Publisher Copyright: {\textcopyright} 2021 Gebril et al.",

year = "2021",

doi = "https://doi.org/10.1523/ENEURO.0011-21.2021",

language = "English (US)",

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T1 - Developmental role of adenosine kinase in the cerebellum

AU - Gebril, Hoda

AU - Wahba, Amir

AU - Zhou, Xiaofeng

AU - Lai, Tho

AU - Alharfoush, Enmar

AU - Dicicco-Bloom, Emanuel

AU - Boison, Detlev

N1 - Funding Information: This work was supported by Dale & Beverly Rice, National Institutes of Health Grants NS065957 and NS103740 (to D.B.), and Citizens United for Research in Epilepsy (CURE Catalyst Award; D.B.). Publisher Copyright: © 2021 Gebril et al.

PY - 2021

Y1 - 2021

N2 - Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner in vitro. In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.

AB - Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhibitor 5-iodotubericine (5-ITU) reduced DNA synthesis of granular neuron precursors in a concentration-dependent manner in vitro. In the developing CB, immunohistochemical studies indicated ADK-L is expressed in immature Purkinje cells and granular neuron precursors, whereas in adulthood, ADK is absent from Purkinje cells, but widely expressed in mature granule neurons and their molecular layer (ML) processes. Furthermore, ADK-L is expressed in developing and mature Bergmann glia in the Purkinje cell layer, and in astrocytes in major cerebellar cortical layers. Together, our data demonstrate an association between neuronal ADK expression and developmental processes of the CB, which supports a functional role of ADK-L in the plasticity of the CB.

KW - Adenosine

KW - Adenosine kinase

KW - Cell proliferation

KW - Cerebellum

KW - Development

KW - Granule neuron precursors

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U2 - https://doi.org/10.1523/ENEURO.0011-21.2021

DO - https://doi.org/10.1523/ENEURO.0011-21.2021

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C2 - 33863781

SN - 2373-2822

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JO - eNeuro

JF - eNeuro

IS - 3

M1 - ENEURO.0011-21.2021

ER -

Developmental role of adenosine kinase in the cerebellum

Abstract

ASJC Scopus subject areas

Keywords

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