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Assessment and Characterization of Hyaloid Vessels in Mice
Published on: May 15, 2019
Disruption of the mouse Jhy gene causes abnormal ciliary microtubule patterning and juvenile hydrocephalus
Oliver K Appelbe1, Bryan Bollman, Ali Attarwala
1Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, United States.
Insights
Genetic mutations causing congenital hydrocephalus, excess cerebrospinal fluid (CSF) in the brain, were identified in mice. This study reveals abnormal ependymal cilia and a novel gene, Jhy, crucial for CSF balance.
Area of Science:
- Developmental Biology
- Genetics
- Neuroscience
Background:
- Congenital hydrocephalus, excess cerebrospinal fluid (CSF) in brain ventricles, affects 1 in 1000 children.
- Human genetic causes of hydrocephalus are largely unknown.
- Animal models suggest a genetic basis for CSF regulation.
Purpose of the Study:
- To investigate the genetic underpinnings of congenital hydrocephalus using a novel mouse model.
- To identify the gene responsible for early-onset hydrocephalus in the Jhy(lacZ) mouse line.
Main Methods:
- Generation of a transgenic mouse model (Jhy(lacZ)) with spontaneous hydrocephalus.
- Autosomal recessive inheritance analysis and phenotypic characterization.
- Morphological and ultrastructural analysis of ependymal cilia.
- Gene identification (4931429I11Rik, named Jhy) and expression analysis.
- Partial rescue of phenotype using bacterial artificial chromosome (BAC) technology.
Main Results:
- Jhy(lacZ/lacZ) mice exhibit early-onset, progressive hydrocephalus with lateral ventricle dilation.
- Abnormal ependymal cilia with altered microtubule structures (9+0 or 8+2) were observed.
- Disruption of the Jhy gene was identified as the cause of hydrocephalus.
- Reduced Jhy transcript and protein levels were confirmed in affected mice.
- Partial rescue of the hydrocephalus phenotype was achieved via BAC introduction.
Conclusions:
- The Jhy gene is essential for normal ependymal cilia function and CSF homeostasis.
- Disruption of Jhy leads to congenital hydrocephalus in mice.
- Further research is needed to elucidate the physiological role of the Jhy protein.
Abstract:
Congenital hydrocephalus, the accumulation of excess cerebrospinal fluid (CSF) in the ventricles of the brain, affects one of every 1000 children born today, making it one of the most common human developmental disorders. Genetic causes of hydrocephalus are poorly understood in humans, but animal models suggest a broad genetic program underlying the regulation of CSF balance. In this study, the random integration of a transgene into the mouse genome led to the development of an early onset and rapidly progressive hydrocephalus. Juvenile hydrocephalus transgenic mice (Jhy(lacZ)) inherit communicating hydrocephalus in an autosomal recessive fashion with dilation of the lateral ventricles observed as early as postnatal day 1.5. Ventricular dilation increases in severity over time, becoming fatal at 4-8 weeks of age. The ependymal cilia lining the lateral ventricles are morphologically abnormal and reduced in number in Jhy(lacZ/lacZ) brains, and ultrastructural analysis revealed disorganization of the expected 9+2 microtubule pattern. Rather, the majority of Jhy(lacZ/lacZ) cilia develop axonemes with 9+0 or 8+2 microtubule structures. Disruption of an unstudied gene, 4931429I11Rik (now named Jhy) appears to underlie the hydrocephalus of Jhy(lacZ/lacZ) mice, and the Jhy transcript and protein are decreased in Jhy(lacZ/lacZ) mice. Partial phenotypic rescue was achieved in Jhy(lacZ/lacZ) mice by the introduction of a bacterial artificial chromosome (BAC) carrying 60-70% of the JHY protein coding sequence. Jhy is evolutionarily conserved from humans to basal vertebrates, but the predicted JHY protein lacks identifiable functional domains. Ongoing studies are directed at uncovering the physiological function of JHY and its role in CSF homeostasis.
