A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System

Geoffrey-Alexander Gimenez; Maurits Romijn; Joëlle van den Herik; Wouter Meijer; Ruben Eggers; Barbara Hobo; Chris I De Zeeuw; Cathrin B Canto; Joost Verhaagen; Daniela Carulli

doi:10.3390/ijms26020819

A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System

Geoffrey-Alexander Gimenez, Maurits Romijn, Joëlle van den Herik, Wouter Meijer, Ruben Eggers, Barbara Hobo, Chris I De Zeeuw, Cathrin B Canto, Joost Verhaagen, Daniela Carulli

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Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out.

Originele taal-2	Engels
Artikelnummer	819
Tijdschrift	International Journal of Molecular Sciences
Volume	26
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.3390/ijms26020819
Status	Gepubliceerd - 19 jan. 2025

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Gimenez, G.-A., Romijn, M., van den Herik, J., Meijer, W., Eggers, R., Hobo, B., De Zeeuw, C. I., Canto, C. B., Verhaagen, J., & Carulli, D. (2025). A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System. International Journal of Molecular Sciences, 26(2), Artikel 819. https://doi.org/10.3390/ijms26020819

@article{f07f2a43fae14c6aa925a77712b9a23e,

title = "A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System",

abstract = "Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out.",

keywords = "Animals, Semaphorin-3A/metabolism, Mice, Cerebellar Nuclei/metabolism, Dependovirus/genetics, Integrases/metabolism, Purkinje Cells/metabolism, Central Nervous System/metabolism, Mice, Inbred C57BL, Choroid Plexus/metabolism, Extracellular Matrix/metabolism, Mice, Knockout, Male, Neurons/metabolism, Genetic Vectors/genetics",

author = "Geoffrey-Alexander Gimenez and Maurits Romijn and {van den Herik}, Jo{\"e}lle and Wouter Meijer and Ruben Eggers and Barbara Hobo and {De Zeeuw}, {Chris I} and Canto, {Cathrin B} and Joost Verhaagen and Daniela Carulli",

year = "2025",

month = jan,

day = "19",

doi = "10.3390/ijms26020819",

language = "English",

volume = "26",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "2",

}

Gimenez, G-A, Romijn, M, van den Herik, J, Meijer, W, Eggers, R, Hobo, B, De Zeeuw, CI , Canto, CB, Verhaagen, J & Carulli, D 2025, 'A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System', International Journal of Molecular Sciences, vol. 26, nr. 2, 819. https://doi.org/10.3390/ijms26020819

A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System. / Gimenez, Geoffrey-Alexander; Romijn, Maurits; van den Herik, Joëlle et al.
In: International Journal of Molecular Sciences, Vol. 26, Nr. 2, 819, 19.01.2025.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

T1 - A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System

AU - Gimenez, Geoffrey-Alexander

AU - Romijn, Maurits

AU - van den Herik, Joëlle

AU - Meijer, Wouter

AU - Eggers, Ruben

AU - Hobo, Barbara

AU - De Zeeuw, Chris I

AU - Canto, Cathrin B

AU - Verhaagen, Joost

AU - Carulli, Daniela

PY - 2025/1/19

Y1 - 2025/1/19

N2 - Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out.

AB - Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out.

KW - Animals

KW - Semaphorin-3A/metabolism

KW - Mice

KW - Cerebellar Nuclei/metabolism

KW - Dependovirus/genetics

KW - Integrases/metabolism

KW - Purkinje Cells/metabolism

KW - Central Nervous System/metabolism

KW - Mice, Inbred C57BL

KW - Choroid Plexus/metabolism

KW - Extracellular Matrix/metabolism

KW - Mice, Knockout

KW - Male

KW - Neurons/metabolism

KW - Genetic Vectors/genetics

U2 - 10.3390/ijms26020819

DO - 10.3390/ijms26020819

M3 - Article

C2 - 39859534

SN - 1661-6596

VL - 26

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 2

M1 - 819

ER -