title: Pa2G4 is a novel Six1 co-factor that is required for neural crest and otic development.
abstract: Mutations in SIX1 and in its co-factor, EYA1, underlie Branchiootorenal Spectrum disorder (BOS), which is characterized by variable branchial arch, otic and kidney malformations. However, mutations in these two genes are identified in only half of patients. We screened for other potential co-factors, and herein characterize one of them, Pa2G4 (aka Ebp1/Plfap). In human embryonic kidney cells, Pa2G4 binds to Six1 and interferes with the Six1-Eya1 complex. In Xenopus embryos, knock-down of Pa2G4 leads to down-regulation of neural border zone, neural crest and cranial placode genes, and concomitant expansion of neural plate genes. Gain-of-function leads to a broader neural border zone, expanded neural crest and altered cranial placode domains. In loss-of-function assays, the later developing otocyst is reduced in size, which impacts gene expression. In contrast, the size of the otocyst in gain-of-function assays is not changed but the expression domains of several otocyst genes are reduced. Together these findings establish an interaction between Pa2G4 and Six1, and demonstrate that it has an important role in the development of tissues affected in BOS. Thereby, we suggest that pa2g4 is a potential candidate gene for BOS.
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Neilson
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Abbruzzesse
authors.affiliation: Department of Biology, Hobart and William Smith Colleges, Geneva, NY, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Kenyon
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bartolo
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Krohn
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Alfandari
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA. Electronic address: samoody@gwu.edu.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Moody
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D007758:Ear, Inner / Q000196:embryology* / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005145:Face / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism*; D054258:Neural Plate / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D012886:Skull / Q000196:embryology / Q000378:metabolism; D014158:Transcription, Genetic; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C521148:PA2G4 protein, Xenopus; C530879:Six1 protein, Xenopus; D029867:Xenopus Proteins
keywords: Branchiootorenal; Ebp1; Eya1; Plfap; SIX1