Specification of Pituitary Cell Lineages by the LIM Homeobox Gene Lhx3

Abstract

During pituitary organogenesis, the progressive differentiation of distinct pituitary-specific cell lineages from a common primordium involves a series of developmental decisions and inductive interactions. Targeted gene disruption in mice showed that Lhx3, a LIM homeobox gene expressed in the pituitary throughout development, is essential for differentiation and proliferation of pituitary cell lineages. In mice homozygous for the Lhx3 mutation, Rathke's pouch formed but failed to grow and differentiate; such mice lacked both the anterior and intermediate lobes of the pituitary. The determination of all pituitary cell lineages, except the corticotrophs, was affected, suggesting that a distinct, Lhx3-independent ontogenetic pathway exists for the initial specification of this lineage.

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

“…The phenotype of mice with a homozygous deletion of Lhx3 reflects the importance of the gene in pituitary and nervous system development (Sheng et al, 1996;Sheng et al, 1997;Sharma et al, 1998). In Lhx3 null mice, which die shortly after birth, a definitive Rathke's pouch forms but fails to develop further and lacks four of the five hormone-secreting cell types, containing only a small population of corticotropes.…”

“…Mice with a homozygous Lhx4 gene disruption die shortly after birth from lung defects; heterozygous animals are apparently unaffected (Li et al, 1994). In both Lhx3 and Lhx4 single gene knockout animals, a definitive Rathke's pouch develops, but development of the pituitary arrests in this pouch stage (Sheng et al, 1996;Sheng et al, 1997). Proliferation appears to be impaired and the anterior pituitary is severely hypoplastic (Sheng et al, 1997).…”

The Nuclear LIM Domain Interactor NLI Mediates Homo- and Heterodimerization of LIM Domain Transcription Factors

“…Inhibition of the direct interaction between the LIM domains of Lhx3 and the Isl1 homeodomain by NLI. Similar double immunoprecipitation experiments to those described for the previous figures were performed except that only two proteins (a FLAG and an HA-epitope tagged) were cotranslated for lanes [1][2][3][4][5][6]. In lane 7, untagged NLI was additionally cotranslated from pcDNA3L, and the reaction volume was correspondingly increased.…”

“…In lane 7, untagged NLI was additionally cotranslated from pcDNA3L, and the reaction volume was correspondingly increased. The upper panel shows panel, lanes [3][4][5]. A higher proportion of the slower migrating component of the Isl1 C terminus doublet was observed when unbound to Lhx3, suggesting that interaction with Lhx3 blocks a major phosphorylation site in Isl1.…”

“…1 and 2). Gene deletion studies in mice have revealed that both LIM homeodomain and LMO proteins are essential for embryonic viability, as well as for the development of motor neurons and interneurons, the pancreas, the pituitary, the head, and erythrocytes (3)(4)(5)(6)(7). Most LIM domain transcription factors have limited patterns of expression, but all have been shown to be expressed within subregions of the developing nervous system (8 -13).…”