PUBLICATION

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice

Authors

Hu, M., Bodnar, B., Zhang, Y., Xie, F., Li, F., Li, S., Zhao, J., Zhao, R., Gedupoori, N., Mo, Y., Lin, L., Li, X., Meng, W., Yang, X., Wang, H., Barbe, M.F., Srinivasan, S., Bethea, J.R., Mo, X., Xu, H., Hu, W.

ID

ZDB-PUB-230707-40

Date

2023

Source

International journal of biological sciences 19: 322632483226-3248 (Journal)

Registered Authors

Mo, Xianming

Keywords

none

MeSH Terms

Animals
Intellectual Disability*/genetics
Intellectual Disability*/metabolism
Mice
Microcephaly*/genetics
Microcephaly*/metabolism
Neurites/physiology
Neurons/metabolism
Zebrafish

(all 9)

PubMed

37416774 Full text @ Int. J. Biol. Sci.

Abstract

Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of NIBP/TRAPPC9, a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mechanisms underlying microcephaly, we developed Nibp/Trappc9-deficient animal models using different techniques, including morpholino knockdown and CRISPR/Cas mutation in zebrafish and Cre/LoxP-mediated gene targeting in mice. Nibp/Trappc9 deficiency impaired the stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones. This deficiency also impaired elongation and branching of neuronal dendrites and axons, without significant effects on neurite initiation or neural cell number/types in embryonic and adult brains. The positive correlation of TRAPPII stability and neurite elongation/branching suggests a potential role for TRAPPII in regulating neurite morphology. These results provide novel genetic/molecular evidence to define patients with a type of non-syndromic autosomal recessive intellectual disability and highlight the importance of developing therapeutic approaches targeting the TRAPPII complex to cure TRAPPopathies.

Genes / Markers

Marker	Marker Type	Name
map2	GENE	microtubule-associated protein 2
mbpb	GENE	myelin basic protein b
neflb	GENE	neurofilament light chain b
sox2	GENE	SRY-box transcription factor 2
trappc9	GENE	trafficking protein particle complex subunit 9

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
map2	AB	standard conditions	Long-pec	brain	ISH	Figure 4
map2	AB	standard conditions	Long-pec	whole organism	RTPCR	Figure 4
map2	AB + MO1-trappc9	control	Long-pec	brain	ISH	Figure 4
map2	AB + MO1-trappc9	control	Long-pec	whole organism	RTPCR	Figure 4
map2	AB + MO2-trappc9	control	Long-pec	brain	ISH	Figure 4
map2	AB + MO2-trappc9	control	Long-pec	whole organism	RTPCR	Figure 4
map2	trappc9^{scu303/scu303} (AB)	standard conditions	Long-pec	brain	ISH	Figure 4
map2	trappc9^{scu303/scu303} (AB)	standard conditions	Long-pec	whole organism	RTPCR	Figure 4
map2	trappc9^{scu304/scu304} (AB)	standard conditions	Long-pec	brain	ISH	Figure 4
map2	trappc9^{scu304/scu304} (AB)	standard conditions	Long-pec	whole organism	RTPCR	Figure 4

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO1-trappc9	control	Long-pec	brain map2 expression decreased distribution, abnormal	Figure 4
AB + MO1-trappc9	control	Long-pec	brain decreased size, abnormal	Fig. S2
AB + MO1-trappc9	control	Long-pec	hindbrain neflb expression decreased distribution, abnormal	Figure 2
AB + MO1-trappc9	control	Long-pec	intertectal commissure axon ab1-tuba labeling decreased distribution, abnormal	Figure 2
AB + MO1-trappc9	control	Long-pec	intertectal commissure axon decreased amount, abnormal	Figure 2
AB + MO1-trappc9	control	Long-pec	intertectal commissure axon decreased length, abnormal	Figure 2
AB + MO1-trappc9	control	Long-pec	midbrain neflb expression decreased distribution, abnormal	Figure 2
AB + MO1-trappc9	control	Long-pec	whole organism map2 expression decreased amount, abnormal	Figure 4
AB + MO1-trappc9	control	Long-pec	whole organism neflb expression decreased amount, abnormal	Figure 2
AB + MO1-trappc9	control	Protruding-mouth	brain mbpb expression decreased distribution, abnormal	Figure 3

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
scu303	Small Deletion	trappc9
scu304	Small Deletion	trappc9
scu305	Small Deletion	trappc9
scu306	Indel	trappc9
scu307	Indel	trappc9

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
trappc9	CRISPR1-trappc9	CRISPR
trappc9	CRISPR2-trappc9	CRISPR
trappc9	MO1-trappc9	MRPHLNO
trappc9	MO2-trappc9	MRPHLNO

Fish

Fish
AB
AB + MO1-trappc9
AB + MO2-trappc9
trappc9^{scu303/scu303} (AB)
trappc9^{scu304/scu304} (AB)
trappc9^{scu305/scu305} (AB)
trappc9^{scu306/scu306} (AB)
trappc9^{scu307/scu307} (AB)

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Hu et al., 2023 ZDB-PUB-230707-40 PMID:37416774

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice

Hu et al., 2023

ZDB-PUB-230707-40
PMID:37416774