Angiopoietin 1 and integrin beta 1b are vital for zebrafish brain development

Abstract

This study aimed at identifying the role of angiopoietin 1 (angpt1) in brain development, the mode of action of angpt1, and the main targets in the zebrafish brain. We investigated embryonic brain angiogenesis and neural development in the angpt1sa14264, itgb1bmi371, tekhu1667 mutant fish, and the effects of transgenic overexpression of angpt1 in the larval brain. Lack of angpt1 was associated with downregulation of tek and upregulation of itgb1b. We found deficiencies in the patterning of proliferation, the vascular network and reticulospinal neurons in the hindbrain, and selective deficiencies in specific neurotransmitter systems. In the angpt1sa14264 and itgb1bmi371 larval brains, using microangiography, retrograde labeling, and immunostaining, we demonstrated that the targeted destruction of angpt1sa14264 and itgb1bmi371 mutant fish caused severe irregular cerebrovascular development, aberrant hindbrain patterning, downregulation of neural proliferation, expansion of the radial glial progenitors, deficiencies of dopaminergic, histaminergic, and GABAergic populations in the larval brain. In contrast, the tekhu1667 mutants regularly grew with no such apparent phenotypes. Neurally overexpressed angpt1 promoted opposite effects by increasing the vascular branching, increasing cell proliferation, and neuronal progenitors. Notably, zebrafish angpt1 showed neurogenic activity independent of its typical receptor tek, indicating the novel role of a dual regulation by angpt1 in embryonic neurogenesis and angiogenesis in zebrafish. The results show that angpt1 and its interaction with itgb1b are crucial in zebrafish brain neuronal and vascular development and suggest that angpt1 through itgb1b can act as a neurogenic factor in the neural proliferation fate in the developing brain.