title: The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice.
abstract: OBJECTIVE
  Several forkhead box (FOX) transcription factor family members have important roles in controlling pancreatic cell fates and maintaining beta cell mass and function, including FOXA1, FOXA2 and FOXM1. In this study we have examined the importance of FOXP1, FOXP2 and FOXP4 of the FOXP subfamily in islet cell development and function.
  
  
  METHODS
  Mice harbouring floxed alleles for Foxp1, Foxp2 and Foxp4 were crossed with pan-endocrine Pax6-Cre transgenic mice to generate single and compound Foxp mutant mice. Mice were monitored for changes in glucose tolerance by IPGTT, serum insulin and glucagon levels by radioimmunoassay, and endocrine cell development and proliferation by immunohistochemistry. Gene expression and glucose-stimulated hormone secretion experiments were performed with isolated islets.
  
  
  RESULTS
  Only the triple-compound Foxp1/2/4 conditional knockout (cKO) mutant had an overt islet phenotype, manifested physiologically by hypoglycaemia and hypoglucagonaemia. This resulted from the reduction in glucagon-secreting alpha cell mass and function. The proliferation of alpha cells was profoundly reduced in Foxp1/2/4 cKO islets through the effects on mediators of replication (i.e. decreased Ccna2, Ccnb1 and Ccnd2 activators, and increased Cdkn1a inhibitor). Adult islet Foxp1/2/4 cKO beta cells secrete insulin normally while the remaining alpha cells have impaired glucagon secretion.
  
  
  CONCLUSIONS
  Collectively, these findings reveal an important role for the FOXP1, 2, and 4 proteins in governing postnatal alpha cell expansion and function.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, 723 Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Spaeth
authors.forename: Chad S
authors.initials: CS
authors.lastname: Hunter
authors.forename: Lauren
authors.initials: L
authors.lastname: Bonatakis
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Catherine A
authors.initials: CA
authors.lastname: French
authors.forename: Ian
authors.initials: I
authors.lastname: Slack
authors.forename: Manami
authors.initials: M
authors.lastname: Hara
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C432918:Foxp2 protein, mouse; C472854:Foxp4 protein, mouse; D007328:Insulin; D012097:Repressor Proteins; D005934:Glucagon