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 hypothalamicpituitary somatotrophic axis.growth hormone ͉ growth hormone-releasing hormone ͉ insulin-like growth factor I ͉ somatotrophs

The emerging role of the Ikaros stem cell factor in the neuroendocrine system

“…GH positivity persists in the intermediate lobe of the lateral wings likely attributable to the lack of melanocorticotrope expansion that normally replaces intermediate lobe somatotrophs during development. Other cell types were not measurably affected; the number and area of immunoreactive thyrotrophs and gonadotrophs were not disproportionately different from those of wild-type littermates (Ezzat et al 2006a).…”

“…Again, to exclude the possibility of a secondary response to immunodeficiency, we performed bone marrow reconstitution studies and showed that hematopoietic replacement does not alter IGF-I levels and restore normal growth. We carried out administration of exogenous GH with a response of circulating IGF-I levels and body weight reflecting somatic growth (Ezzat et al 2006a).…”

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

“…IKAROS is expressed in neuro-epithelial progenitors of the developing striatum, cortical and retinal progenitors, and the developing pituitary (Georgopoulos et al 1992;Ezzat et al 2006;Agoston et al 2007;MartinIbanez et al 2010;Alsio et al 2013). In addition to neuroepithelial cells, HELIOS is also expressed in epidermal keratinocytes (Kelley et al 1998).…”

Transcription factors in the development of medial hypothalamic structures

“…The GHRH lineage is completely dependent upon ASCL1 activity because Ascl1-null embryos have very low expression of genomic screen homeobox 1 (GSH1), a homeobox domain transcription factor necessary for expression of Ghrh (28). A zinc finger containing the transcription factor Ikaros has been found to be necessary for Ghrh expression (12). Interestingly, both GSH1 and Ikaros are similarly expressed in pituitary somatotropes, and loss of either protein results in extreme dwarfism and loss of somatotropes.…”