title: Islet α-, β-, and δ-cell development is controlled by the Ldb1 coregulator, acting primarily with the islet-1 transcription factor.
abstract: Ldb1 and Ldb2 are coregulators that mediate Lin11-Isl1-Mec3 (LIM)-homeodomain (HD) and LIM-only transcription factor-driven gene regulation. Although both Ldb1 and Ldb2 mRNA were produced in the developing and adult pancreas, immunohistochemical analysis illustrated a broad Ldb1 protein expression pattern during early pancreatogenesis, which subsequently became enriched in islet and ductal cells perinatally. The islet-enriched pattern of Ldb1 was similar to pan-endocrine cell-expressed Islet-1 (Isl1), which was demonstrated in this study to be the primary LIM-HD transcription factor in developing and adult islet cells. Endocrine cell-specific removal of Ldb1 during mouse development resulted in a severe reduction of hormone⁺ cell numbers (i.e., α, β, and δ) and overt postnatal hyperglycemia, reminiscent of the phenotype described for the Isl1 conditional mutant. In contrast, neither endocrine cell development nor function was affected in the pancreas of Ldb2(-/-) mice. Gene expression and chromatin immunoprecipitation (ChIP) analyses demonstrated that many important Isl1-activated genes were coregulated by Ldb1, including MafA, Arx, insulin, and Glp1r. However, some genes (i.e., Hb9 and Glut2) only appeared to be impacted by Ldb1 during development. These findings establish Ldb1 as a critical transcriptional coregulator during islet α-, β-, and δ-cell development through Isl1-dependent and potentially Isl1-independent control.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Chad S
authors.initials: CS
authors.lastname: Hunter
authors.forename: Shilpy
authors.initials: S
authors.lastname: Dixit
authors.forename: Tsadok
authors.initials: T
authors.lastname: Cohen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ediger
authors.forename: Crystal
authors.initials: C
authors.lastname: Wilcox
authors.forename: Mark
authors.initials: M
authors.lastname: Ferreira
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.forename: Catherine Lee
authors.initials: CL
authors.lastname: May
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009928:Organ Specificity; D038081:Organogenesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019864:Somatostatin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; C102084:Ldb1 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1