PUBLICATION

Mutations in dock1 disrupt early Schwann cell development

Authors

Cunningham, R.L., Herbert, A.L., Harty, B.L., Ackerman, S.D., Monk, K.R.

ID

ZDB-PUB-180810-2

Date

2018

Source

Neural Development 13: 17 (Journal)

Registered Authors

Monk, Kelly

Keywords

Myelination, Schwann cell development, Zebrafish, dock1

MeSH Terms

Lateral Line System/cytology*
Lateral Line System/embryology
Mutation/genetics*
Embryo, Nonmammalian
Microinjections
Microscopy, Electron, Transmission
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism
Gene Expression Regulation, Developmental/genetics*
Animals, Genetically Modified
Animals
Myelin Basic Protein/metabolism
Luminescent Proteins/genetics
Luminescent Proteins/metabolism
Zebrafish
Age Factors
RNA, Messenger/metabolism
Schwann Cells/physiology*
Schwann Cells/ultrastructure
rac GTP-Binding Proteins/genetics*
rac GTP-Binding Proteins/metabolism
Peripheral Nervous System/cytology
Peripheral Nervous System/embryology

(all 23)

PubMed

30089513 Full text @ Neural Dev.

Abstract

Background In the peripheral nervous system (PNS), specialized glial cells called Schwann cells produce myelin, a lipid-rich insulating sheath that surrounds axons and promotes rapid action potential propagation. During development, Schwann cells must undergo extensive cytoskeletal rearrangements in order to become mature, myelinating Schwann cells. The intracellular mechanisms that drive Schwann cell development, myelination, and accompanying cell shape changes are poorly understood.

Methods Through a forward genetic screen in zebrafish, we identified a mutation in the atypical guanine nucleotide exchange factor, dock1, that results in decreased myelination of peripheral axons. Rescue experiments and complementation tests with newly engineered alleles confirmed that mutations in dock1 cause defects in myelination of the PNS. Whole mount in situ hybridization, transmission electron microscopy, and live imaging were used to fully define mutant phenotypes.

Results We show that Schwann cells in dock1 mutants can appropriately migrate and are not decreased in number, but exhibit delayed radial sorting and decreased myelination during early stages of development.

Conclusions Together, our results demonstrate that mutations in dock1 result in defects in Schwann cell development and myelination. Specifically, loss of dock1 delays radial sorting and myelination of peripheral axons in zebrafish.

Genes / Markers

Figures

Show all Figures

Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
dock1^{stl145/stl145}	standard conditions	Protruding-mouth	posterior lateral line immature Schwann cell	ISH	Fig. 5
WT	standard conditions	Protruding-mouth	posterior lateral line myelinating Schwann cell	ISH	Fig. 5
dock1^{stl145/stl145}; w18Tg; zf15Tg	standard conditions	Long-pec	myelinating Schwann cell nucleus	IFL	Fig. 4
dock1^{stl145/stl145}; w18Tg; zf15Tg	standard conditions	Long-pec	posterior lateral line immature Schwann cell	IFL	Fig. 4
w18Tg; zf15Tg	standard conditions	Long-pec	myelinating Schwann cell nucleus	IFL	Fig. 4
w18Tg; zf15Tg	standard conditions	Long-pec	posterior lateral line immature Schwann cell	IFL	Fig. 4
dock1^{stl145/stl145}; w18Tg; zf15Tg	standard conditions	Long-pec	posterior lateral line immature Schwann cell	IFL	Fig. 4
dock1^{stl145/stl145}; zf15Tg	control	Prim-15	posterior lateral line system immature Schwann cell	IFL	Fig. 4
w18Tg; zf15Tg	standard conditions	Long-pec	posterior lateral line immature Schwann cell	IFL	Fig. 4
zf15Tg	control	Prim-15	posterior lateral line system immature Schwann cell	IFL	Fig. 4

1 - 10 of 24

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
dock1^stl145/+	standard conditions	Pec-fin	posterior lateral line myelination in peripheral nervous system occurrence, normal	Fig. 5
dock1^stl145/+	standard conditions	Pec-fin	posterior lateral line myelination of posterior lateral line nerve axons occurrence, normal	Fig. 5
dock1^stl145/+; dock1^stl365/+	standard conditions	Protruding-mouth	posterior lateral line immature Schwann cell mbpa expression decreased amount, abnormal	Fig. 2
dock1^stl145/+; dock1^stl366/+	standard conditions	Protruding-mouth	posterior lateral line immature Schwann cell mbpa expression decreased amount, abnormal	Fig. 2
dock1^{stl145/stl145}	standard conditions	Long-pec	posterior lateral line Schwann cell migration occurrence, normal	Fig. 4
dock1^{stl145/stl145}	standard conditions	Pec-fin	posterior lateral line myelination in peripheral nervous system delayed, abnormal	Fig. 5
dock1^{stl145/stl145}	standard conditions	Pec-fin	posterior lateral line myelination of posterior lateral line nerve axons delayed, abnormal	Fig. 5
dock1^{stl145/stl145}	standard conditions	Protruding-mouth	posterior lateral line has normal numbers of parts of type posterior lateral line axon, normal	Fig. 3
dock1^{stl145/stl145}	standard conditions	Protruding-mouth	posterior lateral line immature Schwann cell egr2b expression decreased amount, abnormal	Fig. 5
dock1^{stl145/stl145}	standard conditions	Protruding-mouth	posterior lateral line immature Schwann cell mbpa expression decreased amount, abnormal	Fig. 2

1 - 10 of 25

Show

Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
is5Tg	Tg(kdrl:mCherry)	Transgenic Insertion
stl145		Point Mutation	dock1
stl365		Insertion	dock1
stl366		Small Deletion	dock1
w18Tg	Tg(sox10:NLS-Eos)	Transgenic Insertion
zf15Tg	Tg(foxd3:GFP)	Transgenic Insertion

1 - 6 of 6

Show

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
dock1	TALEN1-dock1	TALEN
dock1	TALEN2-dock1	TALEN

Fish

Fish
dock1^{stl145/stl145}
dock1^{stl145/stl145}
dock1^{stl145/stl145}; w18Tg; zf15Tg
dock1^{stl145/stl145}; zf15Tg
dock1^stl145/+
dock1^stl145/+; dock1^stl365/+
dock1^stl145/+; dock1^stl366/+
dock1^{stl365/stl365}
dock1^{stl366/stl366}
dock1^{stl366/stl366}; dock1^{stl365/stl365}

1 - 10 of 13

Show

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
Eos	EFG	Eos
GFP	EFG	GFP
mCherry	EFG	mCherry

Mapping

Cunningham et al., 2018 ZDB-PUB-180810-2 PMID:30089513

Mutations in dock1 disrupt early Schwann cell development

Cunningham et al., 2018

ZDB-PUB-180810-2
PMID:30089513