Specific domains of FoxD4/5 activate and repress neural transcription factor genes to control the progression of immature neural ectoderm to differentiating neural plate

Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, 2300 I Street NW, Washington DC, USA.
Developmental Biology (Impact Factor: 3.55). 03/2012; 365(2):363-75. DOI: 10.1016/j.ydbio.2012.03.004
Source: PubMed


FoxD4/5, a forkhead transcription factor, plays a critical role in establishing and maintaining the embryonic neural ectoderm. It both up-regulates genes that maintain a proliferative, immature neural ectoderm and down-regulates genes that promote the transition to a differentiating neural plate. We constructed deletion and mutant versions of FoxD4/5 to determine which domains are functionally responsible for these opposite activities, which regulate the critical developmental transition of neural precursors to neural progenitors to differentiating neural plate cells. Our results show that up-regulation of genes that maintain immature neural precursors (gem, zic2) requires the Acidic blob (AB) region in the N-terminal portion of the protein, indicating that the AB is the transactivating domain. Additionally, down-regulation of those genes that promote the transition to neural progenitors (sox) and those that lead to neural differentiation (zic, irx) involves: 1) an interaction with the Groucho co-repressor at the Eh-1 motif in the C-terminus; and 2) sequence downstream of this motif. Finally, the ability of FoxD4/5 to induce the ectopic expression of neural precursor genes in the ventral ectoderm also involves both the AB region and the Eh-1 motif; FoxD4/5 accomplishes ectopic neural induction by both activating neural precursor genes and repressing BMP signaling and epidermal genes. This study identifies the specific, conserved domains of the FoxD4/5 protein that allow this single transcription factor to regulate a network of genes that controls the transition of a proliferative neural ectodermal population to a committed neural plate population poised to begin differentiation.

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Available from: Sally A Moody
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    • "It directly activates a transcriptional triad consisting of Gmnn, Zic2 and Sox11, which in turn regulates the more down-stream components that promote the transition to neural stem and neural progenitor cells (Fig. 2). Finally, structure-function analyses of the Foxd4 protein show that it has separate domains in the Nand C-terminal regions that account for its ability to both activate or repress targets (Klein et al., 2013;Neilson et al., 2012). These findings illustrate how a single transcription factor can regulate the transition of immature, NE precursors to neurally-committed stem cells, and then to neural progenitors that are beginning to differentiate. "
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    • "In FoxD3, FoxA1 and FoxA2, Grg binding to the Eh-1 motif plays an important role in repressing downstream targets [41], [42]. Our studies showed that Grg4 binding enhances FoxD4L1 repressive activity, particularly when FoxD4L1 is present at low concentrations, but it does not account for all of the repressive activity [39]. Herein, we identify additional sites that are predicted to contribute to FoxD4L1’s repressive activity. "
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    • "The GRN takes as a starting point early neural induction from which ANP specification evolves. As shown in Fig. 3, Sox3, Otx2, Ern1, Churchill and FoxD4/5 are among the first TFs to be expressed within the epiblast (Albazerchi and Stern, 2007; Neilson et al., 2012; Sheng et al., 2003; Streit et al., 2000; Yan et al., 2009). These genes, in combination with downstream effectors of the Wnt signalling pathway commit the ectoderm to a pre-neural state by inhibiting the expression of BMP4 and other ectodermal genes and by activating the neural determinants Sox2 and Sip1. "
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