Transcriptional repressor foxl1 regulates central nervous system development by suppressing shh expression in zebra fish.
We identified zebra fish forkhead transcription factor l1 (zfoxl1) as a gene strongly expressed in neural tissues such as midbrain, hindbrain, and the otic vesicle at the early embryonic stage. Loss of the function of zfoxl1 effected by morpholino antisense oligonucleotide resulted in defects in midbrain and eye development, and in that of formation of the pectoral fins. Interestingly, ectopic expression of shh in the midbrain and elevated pax2a expression in the optic stalk were observed in foxl1 MO-injected embryos. In contrast, expression of pax6a, which is negatively regulated by shh, was suppressed in the thalamus and pretectum regions, supporting the idea of augmentation of the shh signaling pathway by suppression of foxl1. Expression of zfoxl1-EnR (repressing) rather than zfoxl1-VP16 (activating) resulted in a phenotype similar to that induced by foxl1-mRNA, suggesting that foxl1 may act as a transcriptional repressor of shh in zebra fish embryos. Supporting this notion, foxl1 suppressed isolated 2.7-kb shh promoter activity in PC12 cells, and the minimal region of foxl1 required for its transcriptional repressor activity showed strong homology with the groucho binding motif, which is found in genes encoding various homeodomain proteins. In view of all of our data taken together, we propose zfoxl1 to be a novel regulator of neural development that acts by suppressing shh expression.
Nakada
Chisako
C
Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Satoh
Shinya
S
Tabata
Yoko
Y
Arai
Ken-ichi
K
Watanabe
Sumiko
S
D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology; D005347:Fibroblasts / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D005775:Gastrula / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
D015415:Biomarkers; D051858:Forkhead Transcription Factors; C514257:Foxl1 protein, zebrafish; D053823:Hedgehog Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D029961:Zebrafish Proteins