Zebrafish Cyp1b1 knockout alters eye and brain metabolomic profiles, affecting ocular and neurobehavioral function

Area of Science:

• Genetics and Zebrafish Model Organisms
• Metabolomics and Neurobehavioral Science
• Ocular Development and Disease Genetics

Background:

• Cytochrome P450 1B1 (CYP1B1) is crucial for metabolizing various compounds, including those vital for eye development.
• CYP1B1 is a known causative gene for primary congenital glaucoma (PCG).
• The precise role of CYP1B1 in PCG, related eye disorders, and neurobehavioral functions remains unclear.

Purpose of the Study:

• To investigate the functional consequences of Cyp1b1 loss using a novel CRISPR-Cas9 generated zebrafish mutant line.
• To elucidate the molecular and behavioral impacts of Cyp1b1 deficiency.
• To differentiate visual defects from broader neurological effects in Cyp1b1 mutants.

Main Methods:

• Generation of a Cyp1b1 mutant zebrafish line using CRISPR-Cas9 technology.
• Comprehensive behavioral analyses, including vision-based and sound-based assays.
• Mass spectrometry-based metabolomics and RNA sequencing (transcriptomics) of eye and brain tissues.

Main Results:

• Mutant zebrafish exhibited hyperactivity in vision-based assays but normal responses in sound-based assays.
• Adult mutants showed altered social interactions and modified responses to visual and auditory stimuli.
• Metabolomic and transcriptomic analyses revealed significant alterations in lipid, nucleotide, and amino acid metabolism in the eye and brain.
• Changes in arachidonic and retinoic acid levels were observed, potentially linked to altered CYP enzyme expression.

Conclusions:

• Loss of Cyp1b1 function disrupts metabolic homeostasis and leads to observable neurobehavioral changes.
• While specific ocular defects were not definitively isolated, the study highlights Cyp1b1's broader role in sensory processing and behavior.
• The zebrafish model provides valuable insights into the complex functions of CYP1B1 beyond its known role in glaucoma.