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CMTR2-catalyzed mRNA 2'-O-Methylation Regulates ER Stress, Purkinje

Cell Development and Cerebellar Function

1,2
1
1
Imelda Margaretha Aritonang, Yao-Ming Chang, Akhlaq Hussain, Yi-Shuian
Huang* ,1,2,3

1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
2 Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Taiwan

University and Academia Sinica, Taipei, Taiwan.
3 Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan

* E-mail: yishuian@ibms.sinica.edu.tw

Abstract
Methylation of messenger RNA (mRNA) plays a crucial role in the central nervous system,
yet its regulatory functions during brain development remain incompletely understood. Cap

methyltransferases CMTR1 and CMTR2 catalyze 2'-O-ribose methylation at the first and
second transcribed nucleotides, forming the cap1 (m7GpppNmNN) and cap2
(m7GpppNmNmN) structures, respectively. While CMTR1 is implicated in brain development,
the role of CMTR2 in cerebellar formation has not been defined.

To address this, we generated Cmtr2 conditional knockout (Cmtr2-cKO) mice in neural
progenitors using Nestin-Cre. These mice exhibited cerebellar atrophy and motor deficits, with
reduced thickness of the molecular layer, the dendritic region of Purkinje cells (PCs).
Immunohistochemistry revealed abnormal axonal and dendritic swellings in PCs. Notably,

AAV-mediated reintroduction of wild-type CMTR2 into the cerebellum rescued these
developmental defects, while a catalytically inactive CMTR2 mutant provided partial rescue.
Interestingly, the increased number of dendritic swellings in CMTR2-depleted PCs may be
partially attributed to elevated endoplasmic reticulum (ER) stress. This is supported by the

observation of expanded ER membrane structures within dendritic swellings. Our results
suggest that CMTR2-mediated cap2 methylation is essential for controlling ER stress during
PC development and cerebellar function. Further studies will focus on identifying cap2-
modified mRNAs in neurons to elucidate the molecular mechanisms by which CMTR2

regulates cerebellar development through mRNA cap modification.

Keywords: Cap 2'-O-ribose methylation; Cerebellum; CMTR2; ER stress response; Purkinje

cell

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