CISH has no non-redundant functions in glucose homeostasis or beta cell proliferation during pregnancy in mice.
OBJECTIVE
Increased beta cell proliferation during pregnancy is mediated by the Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signalling pathway in response to increased lactogen levels. Activation of the pathway leads to transcriptional upregulation of Cish (encoding cytokine-inducible SH2 domain-containing protein), a member of the suppressor of cytokine signalling (SOCS) family of genes, forming a negative-feedback loop. Here, we examined whether conditional gene ablation of Cish in the pancreas improves beta cell proliferation and beta cell function during pregnancy in mice.


METHODS
We derived mice with a novel, conditional loxP allele for Cish. Pancreas-specific ablation of Cish was achieved by crossing Cish (loxP/loxP) mice with Pdx1-Cre (Early) mice. Beta cell proliferation was quantified by BrdU labelling. Glucose homeostasis was examined with glucose tolerance tests and determination of plasma insulin levels. The expression of other Socs genes and target genes of p-STAT5 related to beta cell function and beta cell proliferation was determined by quantitative PCR.


RESULTS
There was no difference in beta cell proliferation or glucose homeostasis between the Cish mutant group and the control group. The p-STAT5 protein level was the same in Cish mutant and control mice. Socs2 gene expression was higher in Cish mutant than control mice at pregnancy day 9.5. The expression of other Socs genes was the same between control and mutant mice.


CONCLUSIONS
Our results show that CISH has no non-redundant functions in beta cell proliferation or glucose homeostasis during pregnancy in mice. Socs2 might compensate for the loss of Cish during pregnancy.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Yang
Y
Jiao
Sebastian
S
Rieck
John
J
Le Lay
Klaus H
KH
Kaestner
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
D005947:Glucose; D011388:Prolactin; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; C491409:Socs2 protein, mouse