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Foxh1, a forkhead box transcription factor, was identified by its ability to bind to an activin response element in the promoter region of Xenopus Mix.2 gene . Foxh1 was initially known as FAST-1 (Forkhead Activin Signal Transducer-1). Subsequently, the Foxh1 homologue in mouse (also known as Fast2), as well as in human (FAST2), Xenopus (XFast-1 and XFast-3) and zebrafish (schmalspur) were identified. Foxh1 functions as a transcription factor downstream of TGFβ/activin/nodal signaling. Foxh1 constituitively binds DNA in the absence of TGFβ signals. In the presence of TGFβ/activin/nodal, signaling is initiated by interaction of the ligand with cell surface receptors, ALK5 and TβRII for TGFβ, ALK4 and ActRIIB for activin, and ALK4 and ActRIIB along with the EGF-CFC co-receptors (crypto and criptic) for nodal. Regardless of the initiating ligand, the intracellular domain of the ligand-activated receptor interacts with and phosphorylates the receptor-regulated Smads, Smad2 and Smad3 (known as R-smads). Once phosphorylated the R-Smads interact with Smad4 (co-Smad) and translocate into the nucleus, where the R-Smad/co-Smad complex interacts with Foxh1 to regulate expression of a spectrum of target genes. Studies with the Gsc promoter have suggested that FoxH1 complexes containing Smad2 and Smad4 activate gene expression, with Smad4 also making contact with DNA. In contrast, FoxH1/Smad3/Smad4 complexes, Smad3 interacts with the DNA and the resulting complex is unable to activate transcription . Foxh1 binds directly to DNA through its Forkhead domain and interacts with the R-Smads through its Smad Interaction domain (SID). Foxh1 does not appear to directly interact with Smad4. Although Foxh1 can function in response to all three ligands, during early embryonic development Foxh1 is thought to primarily function in the Nodal signaling pathway. Nodal, a member of TGFβ superfamily of ligands, plays a vital role in early embryonic patterning, including germ layer induction and axis formation. Foxh1 knockout mouse mutant embryos exhibited a range of phenotypes recapitulating to different extents the loss of nodal function (See Genetics), indicating that Foxh1 is important for most of the patterning functions proposed for nodal. In addition, Foxh1 is required in a positive feedback loop that increases nodal expression . Inactivation of Foxh1 does not affect embryonic patterning as severely as the loss of nodal, indicating that additional transcription factors are important downstream of nodal and the Smads. Foxh1 transcription complexes activate Nodal-dependent expression of target genes such as Nodal, Lefty, Goosecoid (Gsc), Mixl1 and Pitx2 (See Targets). However, induction of the Mef2c gene in the anterior heart field also requires cooperation of Nkx2.5 with Foxh1.