PUBLICATION

L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing

Authors

Linneberg, C., Toft, C.L.F., Kjaer-Sorensen, K., Laursen, L.S.

ID

ZDB-PUB-190308-14

Date

2019

Source

Scientific Reports 9: 3716 (Journal)

Registered Authors

Keywords

none

MeSH Terms

Neural Cell Adhesion Molecule L1/chemistry
Neural Cell Adhesion Molecule L1/genetics*
Neural Cell Adhesion Molecule L1/metabolism*
Zebrafish Proteins/chemistry
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism
Brain/growth & development*
Brain/metabolism
Aspartic Acid Endopeptidases/metabolism
Gene Knockout Techniques
Disease Models, Animal
Zebrafish
Proteolysis
Hydrocephalus/genetics*
Hydrocephalus/metabolism
ADAM Proteins/metabolism
Animals
HEK293 Cells
Humans

(all 19)

PubMed

30842511 Full text @ Sci. Rep.

Abstract

Normal brain development depends on tight temporal and spatial regulation of connections between cells. Mutations in L1cam, a member of the immunoglobulin (Ig) superfamily that mediate cell-cell contacts through homo- and heterophilic interactions, are associated with several developmental abnormalities of the nervous system, including mental retardation, limb spasticity, hydrocephalus, and corpus callosum aplasia. L1cam has been reported to be shed from the cell surface, but the significance of this during different phases of brain development is unknown. We here show that ADAM10-mediated shedding of L1cam is regulated by its fibronectin type III (FNIII) domains. Specifically, the third FNIII domain is important for maintaining a conformation where access to a membrane proximal cleavage site is restricted. To define the role of ADAM10/17/BACE1-mediated shedding of L1cam during brain development, we used a zebrafish model system. Knockdown of the zebrafish, l1camb, caused hydrocephalus, defects in axonal outgrowth, and myelination abnormalities. Rescue experiments with proteinase-resistant and soluble L1cam variants showed that proteolytic cleavage is not required for normal axonal outgrowth and development of the ventricular system. In contrast, metalloproteinase-mediated shedding is required for efficient myelination, and only specific fragments are able to mediate this stimulatory function of the shedded L1cam.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO3-l1camb	standard conditions	20-25 somites	medial longitudinal fasciculus defasciculated, abnormal	Fig. S5
AB + MO3-l1camb	standard conditions	Prim-5	primary motor neuron axon extension decreased process quality, abnormal	Fig. 4
AB + MO3-l1camb	standard conditions	Long-pec	fourth ventricle cerebral spinal fluid increased amount, abnormal	Fig. 4
AB + MO3-l1camb	standard conditions	Long-pec	ventricular system cerebral spinal fluid increased amount, abnormal	Fig. 4
AB + MO4-l1camb	standard conditions	20-25 somites	medial longitudinal fasciculus defasciculated, abnormal	Fig. S5
AB + MO4-l1camb	standard conditions	Prim-5	primary motor neuron axon extension decreased process quality, abnormal	Fig. 4
AB + MO4-l1camb	standard conditions	Long-pec	fourth ventricle cerebral spinal fluid increased amount, abnormal	Fig. S6
AB + MO4-l1camb	standard conditions	Long-pec	fourth ventricle cerebral spinal fluid increased amount, abnormal	Fig. 4
AB + MO4-l1camb	standard conditions	Long-pec	ventricular system cerebral spinal fluid increased amount, abnormal	Fig. 4
zf2139Tg + MO3-l1camb	standard conditions	Protruding-mouth	spinal cord oligodendrocyte decreased amount, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
zf2139Tg	Tg2(mbpa:Dendra2)	Transgenic Insertion
zf2140Tg	Tg(mbpa:Dendra2-CAAX)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
l1camb	MO3-l1camb	MRPHLNO
l1camb	MO4-l1camb	MRPHLNO

Fish

Fish
AB
AB + MO3-l1camb
AB + MO4-l1camb
zf2139Tg
zf2139Tg + MO3-l1camb
zf2139Tg + MO4-l1camb
zf2140Tg
zf2140Tg + MO3-l1camb
zf2140Tg + MO4-l1camb

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
Dendra2	EFG	Dendra2

Mapping

Linneberg et al., 2019 ZDB-PUB-190308-14 PMID:30842511

L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing

Linneberg et al., 2019

ZDB-PUB-190308-14
PMID:30842511