Identification of Thymosin β4 as an effector of Hand1-mediated vascular development.

Thymosin β4 is identified as a target of Hand1, essential for vascular development in embryos, with synthetic Tβ4 showing potential to rescue vascular formation in specific models.

Summary and findings

This study investigates the role of Thymosin β4 (Tβ4) as a target of the Hand1 transcription factor in vascular development. The research focuses on the implications of Tβ4 in yolk sac vasculogenesis and embryonic survival in a model of Hand1-null embryos. Administration of synthetic Tβ4 was shown to partially rescue vascular formation.

Abstract

The bHLH transcription factor Hand1 (Heart and neural crest-derived transcript-1) has a fundamental role in cardiovascular development; however, the molecular mechanisms have not been elucidated. In this paper we identify Thymosin β4 (Tβ4/Tmsb4x), which encodes an actin monomer-binding protein implicated in cell migration and angiogenesis, as a direct target of Hand1. We demonstrate that Hand1 binds an upstream regulatory region proximal to the promoter of Tβ4 at consensus Thing1 and E-Box sites and identify both activation and repression of Tβ4 by Hand1, through direct binding within either non-canonical or canonical E-boxes, providing new insight into gene regulation by bHLH transcription factors. Hand1-mediated activation of Tβ4 is essential for yolk sac vasculogenesis and embryonic survival, and administration of synthetic TB4 partially rescues yolk sac capillary plexus formation in Hand1-null embryos. Thus, we identify an in vivo downstream target of Hand1 and reveal impaired yolk sac vasculogenesis as a primary cause of early embryonic lethality following loss of this critical bHLH factor.

Limitations

Not reported in abstract.

Elsewhere in the Thymosin Beta-4 (Tβ4) corpus