Figure 6. ISL1 regulates multiple aspects of pituitary gland development.

ISL1 regulates growth of Rathke’s pouch. ISL1 expression is initially activated throughout the pouch (E10.5) (41). By E11.5, ISL1 expression is restricted to the ventral aspect of Rathke’s pouch (green), where cells begin to differentiate and express CGA. This ISL1 domain is juxtaposed ventrally by FOXA1 expression in the nearby oral ectoderm and dorsally by cyclin D1 (CCND1, yellow) expression in proliferating progenitor cells transitioning from the G₁ to the S phase. In the absence of ISL1 expression, the domain of cyclin D1 expression is expanded and there are ectopic sites of apoptosis (black). ISL1 stimulates specification of gonadotrope and thyrotrope lineages by elevating expression of NR5A1 and FOXL2. ISL1-deficient pituitaries have reduced expression of NR5A1 and FOXL2, but no obvious change in GATA2 or GATA3 expression. The reduction in lineage-specific transcription factor gene expression is associated with differentiation of very few thyrotropes (yellow) and gonadotropes (blue) cells at birth. ISL1 suppresses SOX2-expressing progenitors from adopting alternate cell fates. Loss of ISL1 leads to abnormal expression of FOXA1 (red), atypical localization of GATA3 in the nucleus (blue), and activation of p21 expression (CDKN1A, yellow), which is associated with cell cycle exit (G₀). These cells maintain FOXA1 expression, activate FOXJ1, and execute a ciliogenic, mucinous cell fate, resulting in ciliated and nonciliated RCCs.