An essential role for the hematopoietic transcription factor Ikaros in hypothalamic-pituitary-mediated somatic growth.

ABSTRACT

Ikaros transcription factors play critical functions in the control of lymphohematopoiesis and immune regulation. Family members contain multiple zinc fingers that mediate DNA binding and homooligomerization or heterooligomerization. Ikaros is abundantly expressed in pituitary mammosomatotrophs, where it deacetylates histone 3 sites on the proximal growth hormone (GH) promoter to silence gene expression. Ikaros-null mice display stunted growth with reduced circulating levels of the GH target factor insulin-like growth factor I (IGF-I). Ikaros-deficient mice have small anterior pituitary glands with a disproportionately reduced somatotroph population. Systemic administration of GH results in increased IGF-I levels and enhanced somatic growth. In contrast, reconstitution with WT lymphocytes was not sufficient to rescue the stunted growth phenotype of Ikaros-deficient mice. Ikaros was identified in mouse hypothalamic arcuate nuclei, where it colocalized with GH-releasing hormone (GHRH); in contrast, Ikaros-null mice lack GHRH immunoreactivity in the hypothalamus. Overexpression of Ikaros enhanced GHRH promoter activity and induced endogenous GHRH gene expression. These findings unmask a wider role for Ikaros in the neuroendocrine system, highlighting a critical contribution to the development of the hypothalamic-pituitary somatotrophic axis.