Dachshund homologues play a conserved role in islet cell development.
All metazoans use insulin to control energy metabolism, but they secrete it from different cells: neurons in the central nervous system in invertebrates and endocrine cells in the gut or pancreas in vertebrates. Despite their origins in different germ layers, all of these insulin-producing cells share common functional features and gene expression patterns. In this study, we tested the role in insulin-producing cells of the vertebrate homologues of Dachshund, a transcriptional regulator that marks the earliest committed progenitors of the neural insulin-producing cells in Drosophila. Both zebrafish and mice expressed a single dominant Dachshund homologue in the pancreatic endocrine lineage, and in both species loss of this homologue reduced the numbers of all islet cell types including the insulin-producing β-cells. In mice, Dach1 gene deletion left the pancreatic progenitor cells unaltered, but blocked the perinatal burst of proliferation of differentiated β-cells that normally generates most of the β-cell mass. In β-cells, Dach1 bound to the promoter of the cell cycle inhibitor p27Kip1, which constrains β-cell proliferation. Taken together, these data demonstrate a conserved role for Dachshund homologues in the production of insulin-producing cells.
Kalousova
Anna
A
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Mavropoulos
Anastasia
A
Adams
Bruce A
BA
Nekrep
Nada
N
Li
Zhongmei
Z
Krauss
Stephan
S
Stainier
Didier Y
DY
German
Michael S
MS
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D014157:Transcription Factors / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
C456264:Dach1 protein, mouse; C461682:DachA protein, zebrafish; C461683:DachB protein, zebrafish; C461684:DachC protein, zebrafish; D005136:Eye Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27