PUBLICATION
Loss of FMRP affects ovarian development and behaviour through multiple pathways in a zebrafish model of fragile X syndrome
- Authors
- Rani, R., Sri, N.S., Medishetti, R., Chatti, K., Sevilimedu, A.
- ID
- ZDB-PUB-240507-4
- Date
- 2024
- Source
- Human molecular genetics 33(16): 1391-1405 (Journal)
- Registered Authors
- Chatti, Kiranam, Rani, Rita, Sevilimedu, Aarti, Sri, N Sushma
- Keywords
- FMRP, Fragile X syndrome, oogenesis, reproduction, translation
- MeSH Terms
-
- Animals
- Brain/growth & development
- Brain/metabolism
- Brain/pathology
- Disease Models, Animal*
- Female
- Fragile X Mental Retardation Protein*/genetics
- Fragile X Mental Retardation Protein*/metabolism
- Fragile X Syndrome*/genetics
- Fragile X Syndrome*/metabolism
- Fragile X Syndrome*/pathology
- Gene Expression Regulation, Developmental
- Gene Knockout Techniques
- Humans
- Oocytes/growth & development
- Oocytes/metabolism
- Ovary*/growth & development
- Ovary*/metabolism
- Phenotype
- RNA-Binding Proteins
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 38710511 Full text @ Hum. Mol. Genet.
Citation
Rani, R., Sri, N.S., Medishetti, R., Chatti, K., Sevilimedu, A. (2024) Loss of FMRP affects ovarian development and behaviour through multiple pathways in a zebrafish model of fragile X syndrome. Human molecular genetics. 33(16):1391-1405.
Abstract
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder and the leading genetic cause of autism spectrum disorders. FXS is caused by loss of function mutations in Fragile X mental retardation protein (FMRP), an RNA binding protein that is known to regulate translation of its target mRNAs, predominantly in the brain and gonads. The molecular mechanisms connecting FMRP function to neurodevelopmental phenotypes are well understood. However, neither the full extent of reproductive phenotypes, nor the underlying molecular mechanisms have been as yet determined. Here, we developed new fmr1 knockout zebrafish lines and show that they mimic key aspects of FXS neuronal phenotypes across both larval and adult stages. Results from the fmr1 knockout females also showed that altered gene expression in the brain, via the neuroendocrine pathway contribute to distinct abnormal phenotypes during ovarian development and oocyte maturation. We identified at least three mechanisms underpinning these defects, including altered neuroendocrine signaling in sexually mature females resulting in accelerated ovarian development, altered expression of germ cell and meiosis promoting genes at various stages during oocyte maturation, and finally a strong mitochondrial impairment in late stage oocytes from knockout females. Our findings have implications beyond FXS in the study of reproductive function and female infertility. Dissection of the translation control pathways during ovarian development using models like the knockout lines reported here may reveal novel approaches and targets for fertility treatments.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping