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

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 theangpt1sa14264,itgb1bmi371,tekhu1667mutant fish, and the effects of transgenic overexpression ofangpt1in the larval brain. Lack ofangpt1was associated with downregulation oftekand upregulation ofitgb1b. 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 theangpt1sa14264anditgb1bmi371larval brains, using microangiography, retrograde labeling, and immunostaining, we demonstrated that the targeted destruction ofangpt1sa14264anditgb1bmi371mutant 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, thetekhu1667mutants regularly grew with no such apparent phenotypes. Neurally overexpressedangpt1promoted opposite effects by increasing the vascular branching, increasing cell proliferation, and neuronal progenitors. Notably, zebrafishangpt1showed neurogenic activity independent of its typical receptortek, indicating the novel role of a dual regulation byangpt1in 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.

Chromatin remodeler Brahma safeguards canalization in cardiac mesoderm differentiation

SUMMARYDifferentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1–4. Canalization is essential for stabilizing cell fate, but the mechanisms underlying robust canalization are unclear. Here we show that deletion of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm (encoding Brahma) results in a radical identity switch during directed cardiogenesis of mouse embryonic stem cells (ESCs). Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells subsequently shifted identities, predominantly becoming neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state inducing a fate switch referred to as a saddle-node bifurcation3,4. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of the neurogenic factor POU3F1 and preventing expression of the neural suppressor REST. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction, repressing Pou3f1 and re-establishing a cardiogenic chromatin landscape. Our results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.