Pituitary Expression Of Isl1 Prevents Ectopic, Foxa1 And Foxj1 Mediated Differentiation Of Progenitors Into Rathke'S Cleft Cysts

BANDO H; CAMARANO AC; BRINKMEIER M; YOSHIMOTO K; CAMPER SA; FUJIO S; DE SOUZA FS

New Orleans

Congreso; ENDO 2019; 2019

Endocrine Society

Rathke´s cleft cysts are common intracranial lesions that are thought to originate from embryonic oral epithelium. They can be asymptomatic or cause pituitary dysfunction, headache, visual problems, and diabetes insipidus. We discovered that pituitary-specific deletion of the LIM homeodomain transcription factor Islet 1 (ISL1) in mice causes development of multiple Rathke?s cleft cysts, early in postnatal life, with 100% penetrance. Mouse Rathke´s cleft cysts mimic the histology of human cysts in that they are comprised of single-layered, ciliated epithelial cells that express the characteristic pathologic markers, cytokeratin 8 and acetylated tubulin. Moreover, they lack expression of B-raf, a marker of craniopharyngiomas, another important pituitary pathology of embryological origin. ISL1 deficiency causes increased cell apoptosis and reduced differentiation of progenitors into gonadotropes and thyrotropes. The pituitary-thyroid axis dysfunction accounts for the reduced body size that is especially evident in adolescent mice. RNA-Seq analysis of newborn, mutant mouse pituitaries identified ectopic expression of Foxj1 and Foxa1. FOXJ1 normally drives the ciliogenic gene expression program in multiple tissues. FOXA1 is a pioneer transcription factor that antagonizes epithelial to mesenchymal-like transitions (EMT) by positively regulating E-cadherin expression and maintaining epithelial-like fate. To assess whether our model of Rathke´s cleft cyst formation accurately predicts the mechanisms underlying this pathology in humans, we obtained tissues from patients that underwent surgery for problematic cysts, and we analyzed expression of FOXA1, FOXJ1 and progenitor markers SOX2 and SOX9. We found significant, consistent, ectopic expression of FOXA1 and FOXJ1 in human cysts and variable expression of progenitor markers, mirroring the findings in mice. Together, these studies support a model whereby expression of ISL1 in pituitary progenitors is necessary to drive differentiation into thyrotropes and gonadotropes, and without this essential driver, progenitors can activate FOXA1 and FOXJ1, permitting them to differentiate along an oral epithelial cell fate, producing mucinous cysts. Thus, Isl1 expression in pituitary progenitor cells is necessary to suppress ectopic cell fates. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke´s cleft cysts.