title: A novel role for Pax6 in the segmental organization of the hindbrain.
abstract: Complex patterns and networks of genes coordinate rhombomeric identities, hindbrain segmentation and neuronal differentiation and are responsible for later brainstem functions. Pax6 is a highly conserved transcription factor crucial for neuronal development, yet little is known regarding its early roles during hindbrain segmentation. We show that Pax6 expression is highly dynamic in rhombomeres, suggesting an early function in the hindbrain. Utilization of multiple gain- and loss-of-function approaches in chick and mice revealed that loss of Pax6 disrupts the sharp expression borders of Krox20, Kreisler, Hoxa2, Hoxb1 and EphA and leads to their expansion into adjacent territories, whereas excess Pax6 reduces these expression domains. A mutual negative cross-talk between Pax6 and Krox20 allows these genes to be co-expressed in the hindbrain through regulation of the Krox20-repressor gene Nab1 by Pax6. Rhombomere boundaries are also distorted upon Pax6 manipulations, suggesting a mechanism by which Pax6 acts to set hindbrain segmentation. Finally, FGF signaling acts upstream of the Pax6-Krox20 network to regulate Pax6 segmental expression. This study unravels a novel role for Pax6 in the segmental organization of the early hindbrain and provides new evidence for its significance in regional organization along the central nervous system.
authors.affiliation: Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, The Robert H. Smith Faculty of Agriculture, Food and Environment, 76100 Rehovot, Israel.
authors.forename: Galya
authors.initials: G
authors.lastname: Kayam
authors.forename: Ayelet
authors.initials: A
authors.lastname: Kohl
authors.forename: Zohar
authors.initials: Z
authors.lastname: Magen
authors.forename: Yuval
authors.initials: Y
authors.lastname: Peretz
authors.forename: Karen
authors.initials: K
authors.lastname: Weisinger
authors.forename: Avi
authors.initials: A
authors.lastname: Bar
authors.forename: Orna
authors.initials: O
authors.lastname: Novikov
authors.forename: Claude
authors.initials: C
authors.lastname: Brodski
authors.forename: Dalit
authors.initials: D
authors.lastname: Sela-Donenfeld
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D001931:Brain Mapping / Q000379:methods; D049109:Cell Proliferation; D002642:Chick Embryo; D003513:Cycloheximide / Q000494:pharmacology; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D018274:Electroporation / Q000379:methods; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017403:In Situ Hybridization; D051258:MafB Transcription Factor / Q000378:metabolism; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D051767:Early Growth Response Protein 2; D005136:Eye Proteins; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; C489833:Hoxa2 protein, mouse; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; D003513:Cycloheximide