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Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease
- Source :
- Neurobiology of Disease, Neurobiology of Disease, Vol 85, Iss, Pp 35-48 (2016)
- Publisher :
- The Authors. Published by Elsevier Inc.
-
Abstract
- Pantothenate Kinase Associated Neurodegeneration (PKAN) is an autosomal recessive disorder with mutations in the pantothenate kinase 2 gene (PANK2), encoding an essential enzyme for Coenzyme A (CoA) biosynthesis. The molecular connection between defects in this enzyme and the neurodegenerative phenotype observed in PKAN patients is still poorly understood. We exploited the zebrafish model to study the role played by the pank2 gene during embryonic development and get new insight into PKAN pathogenesis. The zebrafish orthologue of hPANK2 lies on chromosome 13, is a maternal gene expressed in all development stages and, in adult animals, is highly abundant in CNS, dorsal aorta and caudal vein. The injection of a splice-inhibiting morpholino induced a clear phenotype with perturbed brain morphology and hydrocephalus; edema was present in the heart region and caudal plexus, where hemorrhages with reduction of blood circulation velocity were detected. We characterized the CNS phenotype by studying the expression pattern of wnt1 and neurog1 neural markers and by use of the Tg(neurod:EGFP/sox10:dsRed) transgenic line. The results evidenced that downregulation of pank2 severely impairs neuronal development, particularly in the anterior part of CNS (telencephalon). Whole-mount in situ hybridization analysis of the endothelial markers cadherin-5 and fli1a, and use of Tg(fli1a:EGFP/gata1a:dsRed) transgenic line, confirmed the essential role of pank2 in the formation of the vascular system. The specificity of the morpholino-induced phenotype was proved by the restoration of a normal development in a high percentage of embryos co-injected with pank2 mRNA. Also, addition of pantethine or CoA, but not of vitamin B5, to pank2 morpholino-injected embryos rescued the phenotype with high efficiency. The zebrafish model indicates the relevance of pank2 activity and CoA homeostasis for normal neuronal development and functioning and provides evidence of an unsuspected role for this enzyme and its product in vascular development.<br />Highlights • Zebrafish pank2 gene is highly expressed in the CNS and the main vascular structures. • Pank2 down-regulation severely affects the development of the forebrain. • Pank2 down-regulation affects the dorsal aorta, caudal vein and inter-somitic vessels. • Pantethine and Coenzyme A restore the normal development in the absence of pank2 expression.
- Subjects :
- 0301 basic medicine
Pathology
medicine.medical_specialty
animal structures
Morpholino
Transgene
SOX10
Molecular Sequence Data
Coenzyme A
NBIA
Neurodegeneration
Pank2
Pantethine
Zebrafish
Neurology
Biology
Cardiovascular System
Nervous System
Pantothenate kinase-associated neurodegeneration
Article
lcsh:RC321-571
Animals, Genetically Modified
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
Humans
Amino Acid Sequence
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Pantothenate Kinase-Associated Neurodegeneration
NeuroD
Sequence Homology, Amino Acid
PANK2
biology.organism_classification
medicine.disease
Phenotype
Cell biology
Disease Models, Animal
Phosphotransferases (Alcohol Group Acceptor)
030104 developmental biology
Gene Knockdown Techniques
COS Cells
embryonic structures
HeLa Cells
Subjects
Details
- Language :
- English
- ISSN :
- 09699961
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Disease
- Accession number :
- edsair.doi.dedup.....5b6d889d080a4b557f8b5b96dca0d7a3
- Full Text :
- https://doi.org/10.1016/j.nbd.2015.10.010