title: Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8).
abstract: Atonal Homolog 8 (Atoh8) is a basic helix-loop-helix (bHLH) transcription factor that is highly conserved across species and expressed in multiple tissues during embryogenesis. In the developing pancreas, Atoh8 is expressed in endocrine progenitors but declines in hormone-positive cells, suggesting a role during early stages of the endocrine differentiation program. We previously generated a whole-body Atoh8 knockout but early lethality of null embryos precluded assessment of Atoh8 functions during organ development. Here we report the generation of a conditional Atoh8 knockout mouse strain by insertion of two loxP sites flanking exon 1 of the Atoh8 gene. Pancreas-specific Atoh8 knockout (Atoh8 Δpanc) mice were obtained by mating this strain with a Pdx1-Cre transgenic line. Atoh8 Δpanc mice were born at the expected mendelian ratio and showed normal appearance and fertility. Pancreas weight and gross pancreatic morphology were normal. All pancreatic cell lineages were present, although endocrine δ (somatostatin) cells were modestly augmented in Atoh8 Δpanc as compared to control neonates. This increase did not affect whole-body glucose tolerance in adult knockout animals. Gene expression analysis in embryonic pancreases at the time of the major endocrine differentiation wave revealed modest alterations in several early endocrine differentiation markers. Together, these data argue that Atoh8 modulates activation of the endocrine program but it is not essential for pancreas formation or endocrine differentiation in the mouse. Given the ubiquitous expression pattern of Atoh8, the availability of a mouse strain carrying a conditional allele for this gene warrants further studies using temporally regulated Cre transgenic lines to elucidate time or cell-autonomous functions of Atoh8 during development and in the adult.
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ejarque
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Mir-Coll
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.affiliation: Department of Medicine, Diabetes Center, University of California, San Francisco, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.affiliation: Diabetes Research Program, Child and Family Research Institute, Vancouver, Canada.|Department of Surgery, University of British Columbia, Vancouver, Canada.
authors.forename: Francis C
authors.initials: FC
authors.lastname: Lynn
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Gasa
mesh_terms: D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D007328:Insulin; C449163:Atoh8 protein, mouse