title: Transcriptional regulation of TLX2 and impaired intestinal innervation: possible role of the PHOX2A and PHOX2B genes.
abstract: TLX2 (also known as HOX11L1, Ncx and Enx) is a transcription factor playing a crucial role in the development of the enteric nervous system, as confirmed by mice models exhibiting intestinal hyperganglionosis and pseudo-obstruction. However, congenital defects of TLX2 have been excluded as a major cause of intestinal motility disorders in patients affected with intestinal neuronal dysplasia (IND) or pseudo-obstruction. After demonstrating the direct regulation of TLX2 expression by the homeoprotein PHOX2B, in the present work, we have focused on its paralogue PHOX2A. By co-transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation, we have demonstrated that PHOX2A, like PHOX2B, is involved in the cascade leading to TLX2 transactivation and presumably in the intestinal neuronal differentiation. Based on the hypothesis that missed activation of the TLX2 gene induces the development of enteric nervous system defects, PHOX2A and PHOX2B have been regarded as novel candidate genes involved in IND and pseudo-obstruction and consequently analyzed for mutations in a specific set of 26 patients. We have identified one still unreported PHOX2A variant; however, absence of any functional effect on TLX2 transactivation suggests that regulators or effectors other than the PHOX2 genes must act in the same pathway, likely playing a non redundant and direct role in the pathogenesis of such enteric disorders.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto G Gaslini, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Borghini
authors.forename: Marco
authors.initials: M
authors.lastname: Di Duca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Santamaria
authors.forename: Manuela
authors.initials: M
authors.lastname: Vargiolu
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bachetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Cargnin
authors.forename: Alessio
authors.initials: A
authors.lastname: Pini Prato
authors.forename: Roberto
authors.initials: R
authors.lastname: De Giorgio
authors.forename: Margherita
authors.initials: M
authors.lastname: Lerone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Stanghellini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Jasonni
authors.forename: Diego
authors.initials: D
authors.lastname: Fornasari
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007422:Intestines / Q000294:innervation*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; C491061:PHOX2A protein, human; C491534:TLX2 protein, human; D014157:Transcription Factors