Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas.
Most insulin-producing beta-cells in the fetal mouse pancreas arise during the secondary transition, a wave of differentiation starting at embryonic day 13. Here, we show that disruption of homeobox gene Nkx6.1 in mice leads to loss of beta-cell precursors and blocks beta-cell neogenesis specifically during the secondary transition. In contrast, islet development in Nkx6. 1/Nkx2.2 double mutant embryos is identical to Nkx2.2 single mutant islet development: beta-cell precursors survive but fail to differentiate into beta-cells throughout development. Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation.
Sander
M
M
Hormone Research Institute, University of California San Francisco, San Francisco, CA 94143-0534, USA.
Sussel
L
L
Conners
J
J
Scheel
D
D
Kalamaras
J
J
Dela Cruz
F
F
Schwitzgebel
V
V
Hayes-Jordan
A
A
German
M
M
D000818:Animals; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010179:Pancreas / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins
D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715627:Nkx2-2 protein, mouse; C491328:Nkx6-1 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish