Maternal thyroid hormone is required to develop the hindbrain vasculature in zebrafish

TL;DR

Maternal thyroid hormone is essential for developing blood vessels in the hindbrain of zebrafish embryos.

Contribution

The study reveals that maternal T3 regulates vegfaa expression via pax6a+ neuroprogenitor cells to guide hindbrain vasculature development.

Findings

Maternal T3 regulates vegfaa expression in the hindbrain.

Hindbrain neurons are not the source of vegfaa; instead, pax6a+ neuroprogenitor cells instruct central artery ingression.

Zebrafish Mct8 KD/KO models show impaired hindbrain vasculature due to disrupted MT3 signaling.

Abstract

Thyroid hormone (TH) signaling is important and necessary for proper neurodevelopment. Inadequate levels of maternally derived THs (MTH) supply affect target gene expression profiles, which are fundamental for the brain’s normal growth, maturation, and function. The monocarboxylate transporter 8 (SLC16A2, MCT8) is the main TH transporter present in the brain during embryonic development, and mutations in this transporter lead to a rare and debilitating human condition known as the Allan-Herndon-Dudley Syndrome (AHDS). This mutation affects the capacity for intracellular transport of the hormone, leading to impaired brain development that constitutes the main pathophysiological basis of AHDS. Like humans, zebrafish embryos express slc16a2 that transports exclusively T3 at zebrafish physiological temperature. Studies in zebrafish Mct8 knockdown (KD) models found impaired hindbrain vasculature development. Here, using zebrafish Mct8 KD and knockout (KO) models, we shed light on the maternal T3 (MT3)-dependent developmental mechanism behind hindbrain vasculature development. We first demonstrate that MT3-regulates hindbrain vegfaa expression. We provide evidence that hindbrain neurons are not the source of vegfaa, instead, restricted pax6a+ neuroprogenitor cells (NPCs) instruct central arteries (CtAs) ingression into the hindbrain. Therefore, MT3 acts as an integrator, providing the regulatory cues necessary for the timely ingression of the CtAs into the hindbrain.

Zebrafish AHDS models reveals an important role for maternal thyroid hormone in establishing the hindbrain-blood-barrier via vegfaa signaling regulation in pax6a neuroprogenitors.

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