Thyroid hormone receptor beta mutations alter photoreceptor development and function in Danio rerio (zebrafish)

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Thyroid hormone receptors play vital roles in vertebrate development and physiology.
• Thyroid hormone receptor beta 2 (trβ2), a splice variant of thrb, is implicated in visual system development.
• Specific functions of trβ2 in cone photoreceptor development require further elucidation.

Purpose of the Study:

• To investigate the role of trβ2 in zebrafish cone photoreceptor development and function.
• To characterize the effects of trβ2 mutations on retinal structure, function, and behavior.

Main Methods:

• CRISPR-Cas9 gene editing was used to generate trβ2 mutants in zebrafish.
• Electrophysiological recordings (ERG) were performed to assess cone responses.
• Behavioral assays (optomotor, optokinetic reflexes) were used to evaluate visual function.
• Immunohistochemistry and transgenic reporters were employed to examine cone opsin expression and trβ2 activation.

Main Results:

• Two distinct N-terminus trβ2 mutants were generated: a frameshift deletion (6BP+1) and an in-frame deletion (3BP).
• The 6BP+1 mutant exhibited a complete loss of red cone ERG response and behavioral deficits in red light perception.
• Both larval and adult 6BP+1 mutants showed altered cone opsin gene expression, with reduced red opsin and increased UV opsin activity.
• Antibody staining revealed absence of red-cone opsins and arrestin3a in the 6BP+1 mutant.

Conclusions:

• trβ2 is essential for the proper development and function of red-cones in zebrafish.
• Loss of trβ2 function leads to a failure in red cone maturation and impacts visual processing of long wavelengths.
• These findings highlight the critical role of trβ2 in regulating cone photoreceptor subtype specification and function.