Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Abstract

The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

Figure 1

Regulation of anterior pituitary gland development by signaling proteins and transcription factors. Inductive signals between the ventral diencephalon (DIEN) and the oral ectoderm/anterior neural ridge (OE) precede formation of a rudimentary Rathke’s pouch (rRP, the precursor of the adenohypophysis from which the anterior pituitary develops). Subsequently, a definitive, closed Rathke’s pouch (dcRP) forms. The mature pituitary gland has three main components: the anterior pituitary lobe (AP), the intermediate pituitary (IP), and the posterior pituitary (PP).

Figure 2

The LHX3/LHX4 LIM-homeodomain protein family. A. The domain structure of human (Hs) LHX3a/b proteins and comparison to human LHX4. Percent identity between key domains is shown and the overall identity is in parentheses. LSD = LIM3/4-specific domain. B. Conservation of LHX3/LIM3-class proteins. The overall structure and percent identity of key domains is shown for human, rhesus macaque (Ma), chimp (Pt), cow (Bt), pig (Ss), mouse (Mm), opossum (Md), zebrafish (Dr), chicken (Gg), African clawed frog (Xl), and fruit fly (Dm). L1, L2 = LIM domains; HD = homeodomain. Protein sequences were retrieved from the GenBank, Swiss-Prot, and TIGR databases. C. Conservation of LHX4 proteins. The overall structure and percent identity of key domains is shown for human, chimp, cow, dog (Cf), mouse, opossum, and zebrafish.