Wnt signaling inhibitors regulate the transcriptional response to morphogenetic Shh-Gli signaling in the neural tube.
Shh-Gli signaling controls cell fates in the developing ventral neural tube by regulating the patterned expression of transcription factors in neural progenitors. However, the molecular mechanisms that limit target gene responses to specific domains are unclear. Here, we show that Wnt pathway inhibitors regulate the threshold response of a ventral Shh target gene, Nkx2.2, to establish its restricted expression in the ventral spinal cord. Identification and characterization of an Nkx2.2 enhancer reveals that expression is directly regulated by positive Shh-Gli signaling and negative Tcf repressor activity. Our data indicate that the dorsal limit of Nkx2.2 is controlled by Tcf4-mediated transcriptional repression, and not by a direct requirement for high-level Shh-Gli signaling, arguing against a simple model based on differential Gli factor affinities in target genes. These results identify a transcriptional mechanism that integrates graded Shh and Wnt signaling to define progenitor gene expression domains and cell fates in the neural tube.
Lei
Qiubo
Q
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, 08854, USA.
Jeong
Yongsu
Y
Misra
Kamana
K
Li
Shike
S
Zelman
Alice K
AK
Epstein
Douglas J
DJ
Matise
Michael P
MP
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers / Q000032:analysis; D002490:Central Nervous System / Q000378:metabolism*; D002645:Chickens; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D005136:Eye Proteins / Q000235:genetics; D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D039422:Integrin alpha3 / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000737:chemistry; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; D005136:Eye Proteins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D039422:Integrin alpha3; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C000715627:Nkx2-2 protein, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C465570:Shh protein, mouse; D051820:TCF Transcription Factors; C090743:Tcf4 protein, mouse; D015534:Trans-Activators; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; C000715630:nkx2.2b protein, zebrafish