Disease relevance of Hesx1

• Transgenic mice lacking Hesx1 exhibit a phenotype comprising variable anterior CNS defects, such as a reduced prosencephalon, abnormalities in the corpus callosum and septum pellucidum, anophthalmia or microphthalmia, defective olfactory development and bifurcations in Rathke's pouch with pituitary dysplasia [1].
• Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders [2].

High impact information on Hesx1

• During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland [3].
• In amphibians, Spemann's organizer, which is homologous to the node, partially overlaps with anterior endoderm cells expressing homologues of the AVE markers cerberus, Hex and Hesx1 [4].
• Furthermore, Hesx1-mediated repression coordinates a negative feedback loop with FGF8/FGF10 signaling in the ventral diencephalon, required to prevent induction of multiple pituitary glands from oral ectoderm [5].
• During the development of the pituitary gland, two highly related paired-like homeodomain factors, a repressor, Hesx1/Rpx and an activator, Prop-1, are expressed in sequential, overlapping temporal patterns [5].
• Here, we found that, in mice doubly mutant for the basic helix-loop-helix genes Hes1 and Hes3, the midbrain and anterior hindbrain structures are missing without any significant cell death [6].

Biological context of Hesx1

• TheRpx/Hesx1 homeobox gene is expressed during gastrulation in the anterior visceral and definitive endoderm and the cephalic neural plate [7].
• The homeobox gene Hesx1 is expressed in the anterior visceral endoderm (AVE), anterior axial mesendoderm (AME), and anterior neural ectoderm (ANE) during early mouse embryogenesis [8].
• Removal of endoderm cells expressing Hesx1 during the earlier stages of gastrulation either prevents or severely curtails the later expression of Hesx1 in ectoderm and neurectoderm, but does not affect gene expression in more caudal regions of the developing CNS [9].
• These sites of expression are consistent with a role for Hesx1 in the regulation of developmental decisions in the early mouse embryo and during fetal hematopoiesis [10].
• Hesx1 is expressed as two transcripts of 1.0 and 1.2 kilobases which encode an identical 185 amino acid open reading frame [10].

Anatomical context of Hesx1

• Previous studies have shown that Hesx1 is essential for normal murine forebrain development [8].
• However, transcripts for both genes were markedly reduced by the early somite stage, about 24 h after Hesx1 is first expressed in the ANE [8].
• In contrast, injection of Hesx1(-/-) ES cells into wild-type blastocysts gave rise to chimeras with forebrain defects similar to those observed in the Hesx1(-/-) mutants [8].
• In this paper we report the molecular characterization and expression of a novel murine homeobox sequence, Hesx1, isolated from pluripotent embryonic stem cells [10].
• Hesx1 expression was down-regulated during embryonic stem cell differentiation and was detected in tissue-specific RNA samples derived from the embryonic liver, and at lower levels in viscera, amnion, and yolk sac [10].

Associations of Hesx1 with chemical compounds

• Since cycloheximide treatment did not inhibit induction of HES1 mRNA, the HES1 promoter appears to be a primary target of activated Notch [11].
• Neither treatment with combined (alpha CD3)/(alpha CD28) antibodies nor the combination of the phorbol ester PMA and calcium ionophore ionomycin affects expression of Deltex in immature thymocytes; however, PMA/ionomycin treatment does downregulate expression of HES-1, an affect mostly mediated by ionomycin [12].

Regulatory relationships of Hesx1

• RNA in situ hybridization analysis showed that the AVE and AME markers Cerrl, Lim1, and Shh were normally expressed in 6.5- and 7.5-dpc Hesx1(-/-) mutants [8].
• In addition, both ligands transmitted signal through the CBF-1-dependent pathway and stimulated the expression of HES-1, a direct target of Notch pathway [13].
• These results indicate that Pref-1 expressed by TE cells and HES-1 expressed by thymocytes are critically involved in supporting thymocyte cellularity [14].

Other interactions of Hesx1

• Prop1 and Hesx1 are also important for normal shape of the pituitary primordium, but their expression is unaltered in the Wnt5a mutants [15].
• The analysis of the Hex and Hesx1 mutant mice has revealed that the lack of these genes has little or no effect on the early steps of anterior neural induction [16].
• RESULTS: In situ hybridization studies show that the onset of expression of the homeobox-containing gene Hesx1 coincides with the formation of the primitive streak, but occurs on the opposite side of the embryo, in a small domain of anterior endoderm [9].
• The df mutants fail to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands is reduced by e14 [17].
• These results suggest that MATH-1 may be a target of HES-1 and play a role in the differentiation of subsets of neural cells by activating E box-dependent transcription [18].

Analytical, diagnostic and therapeutic context of Hesx1

• Here, we have investigated the requirement of Hesx1 in the AVE, AME, and ANE using chimeric and in situ hybridization analyses to understand better the nature of the forebrain defects [8].
• Using a semiquantitative RTPCR approach, we show that both Deltex and HES-1 transcriptional levels are developmentally regulated as thymocytes mature from the earliest CD4/CD8 double negative thymocyte stage, through the intermediate CD4/CD8 double positive stage, and finally to the mature CD4 or CD8 single positive stage [12].

References