# Role of Pacs2 in central nervous system myelination

> **NIH NIH R21** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $438,625

## Abstract

Project Summary
Myelination of the central nervous system (CNS) by oligodendrocytes (OLs) is essential for the development
and function of the CNS. Myelin develops in the CNS as OL precursor cells (OPCs) differentiate into OLs,
highlighting OL differentiation as a key event for CNS myelination. Myrf is a master transcription factor of OL
differentiation and CNS myelination. Conditional knockout (cKO) of Myrf in OL lineage cells leads to complete
arrest of OL maturation and lethal dysmyelination. Apparently, the indispensable role of Myrf reflects that of
Myrf target genes in the myelination process. To find novel Myrf targets that may play a critical role in OL
development, we performed an RNA-seq experiment where we acutely knocked out Myrf in differentiating OLs.
As expected, the expression of many genes that are crucial for OL differentiation and CNS myelination went
down significantly upon acute Myrf knockout. Unexpectedly, however, a gene ontology analysis revealed that
Myrf specifically activates the expression of genes related to cell projection, synapse, and intracellular
transport in pre-myelinating OLs. Further, it suggested that molecular machineries involved in axon elongation
may propel the growth of OL processes, which contact axons and eventually form myelin sheaths. Studying
genes that belong to these categories may provide a novel insight into OL differentiation and CNS myelination.
In this regard, we decided to focus on Pacs2 (phosphofurin acidic cluster sorting protein 2), which was
significantly down-regulated upon acute Myrf knockout. Pacs2 is a multifunctional protein that plays an
important role in diverse processes such as endoplasmic reticulum-mitochondria contact and cargo sorting and
transport. PACS2 mutations have been linked to human neurodevelopmental disorders, including a syndromic
form of autism. Remarkably, Pacs2 is mainly expressed by OLs in the CNS. Together with the RNA-seq finding
that Pacs2 is a putative Myrf target, these observations suggest that Pacs2 may be required for OL
development and CNS myelination and that PACS2 dysfunction in OL lineage cells may contribute to the
pathogenesis of autism. In support of these hypotheses, our preliminary study found that Pacs2 is required for
the in vitro differentiation of mouse OPCs, and Pacs2 expression was significantly downregulated in several
autism mouse models where myelin deficiency was observed. Moreover, Pacs2 whole-body knockout mice
exhibited neurological phenotypes. Currently, little is known about the role of Pacs2 in in vivo OL development
and CNS myelination. This project intends to address it by deleting Pacs2 in OL lineage cells through the Cre-
loxP approach.

## Key facts

- **NIH application ID:** 10284160
- **Project number:** 1R21NS123775-01
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** YUNGKI PARK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,625
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284160

## Citation

> US National Institutes of Health, RePORTER application 10284160, Role of Pacs2 in central nervous system myelination (1R21NS123775-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10284160. Licensed CC0.

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