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

• Published in: Developmental biology 2012-05, Vol.365 (2), p.363-375
• Main Authors: Neilson, Karen M., Klein, Steven L., Mhaske, Pallavi, Mood, Kathy, Daar, Ira O., Moody, Sally A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Differentiation; Ectoderm - cytology; Ectoderm - embryology; Ectoderm - metabolism; Forkhead Transcription Factors - chemistry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; foxD4; foxD4L1; gene expression regulation; Gene Expression Regulation, Developmental; genes; Humans; irx1; irx2; irx3; Mice; Molecular Sequence Data; mutants; Neural induction; Neural Plate - cytology; Neural Plate - embryology; Neural Plate - metabolism; Protein Structure, Tertiary; sox11; sox2; sox3; soxD; Transcription; transcription factors; Transcriptional Activation; Xenopus; Xenopus Proteins - chemistry; Xenopus Proteins - genetics; Xenopus Proteins - metabolism; zic1; zic2; zic3
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2012.03.004

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. ► FoxD4/5 up-regulates gem and zic2 via the Acidic blob in the N-terminus. ► Down-regulation of sox, zic, irx genes involves Groucho binding to an Eh-1 motif. ► Down-regulation of some zic and irx genes involves additional C-terminal regions. ► Activating and repressing domains are required for ectopic neural induction. ► These domains are conserved across vertebrates including human.