The Homeobox Gene Hesx1 Is Required in the Anterior Neural Ectoderm for Normal Forebrain Formation

Abstract

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. Previous studies have shown that Hesx1 is essential for normal murine forebrain development. Hesx1 homozygous mutants showed variable forebrain truncations ranging from mild to severe lack of forebrain tissue. 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. Chimeric embryos composed predominantly of Hesx1(+/+) cells developing within Hesx1(-/-) visceral endoderm showed no evident forebrain abnormalities. 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. 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. Expression of the ANE markers Six3 and Rax/Rx was also unperturbed in the Hesx1(-/-) mutants from late gastrula to late headfold stages. However, transcripts for both genes were markedly reduced by the early somite stage, about 24 h after Hesx1 is first expressed in the ANE. Therefore, Hesx1 seems to be required autonomously in the ANE for normal forebrain formation.

Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair

“…On the contrary, many other genes expressed in the pharynx, such as Pax9 (Peters et al, 1998), Pax1 (Wallin et al, 1996), Hoxa-3 (Manley and Capecchi, 1995), Fgf3 (Wendling et al, 2000), Fgf8 (Crossley and Martin, 1995), Hex (Martinez Barbera et al, 2000), are expressed in the endodermal layer of some or all pharyngeal pouches in addition to other tissues. Hence, TTF-2 is a useful marker for the epithelial component of all the structures originating from arches and wall of pharynx: thyroid, tongue, epiglottis, palate, and oesophagus; indeed it is absent in the laryngotracheal groove and its derivatives, trachea, and lungs.…”

Zebrafish hhex regulates liver development and digestive organ chirality

“…Targeted disruption of hhex perturbs growth and differentiation of the mammalian liver primordium (Keng et al, 2000;Martinez Barbera et al, 2000). However, hhex activity is not required for the specification of the prehepatic gut endoderm.…”

“…However, hhex activity is not required for the specification of the prehepatic gut endoderm. The liver diverticulum buds from the gut of hhex mutants, although cells within the diverticulum fail to migrate into the septum transversum (Keng et al, 2000;Martinez Barbera et al, 2000). As a result, the liver remnant in hhex mutants lacks hepatocytes and biliary cells and instead is comprised of hematopoietic precursors that normally reside in the liver, surrounded by the liver capsule (Keng et al, 2000).…”

“…Roles for hhex in embryonic and forebrain patterning (Brickman et al, 2000;Martinez Barbera et al, 2000), and thyroid (Martinez Barbera et al, 2000), and hematopoietic (Keng et al, 2000) development have been described. hhex appears to function as a transcriptional repressor in early development (Brickman et al, 2000;Ho et al, 1999;Tanaka et al, 1999), although recent data suggest it also functions as a transcriptional activator (Denson et al, 2000).…”

Molecular and developmental biology of the hemangioblast

“…In Hex mutant embryos, Hex is required for definitive endodermal organs (Keng et al, 2000;Martinez Barbera et al, 2000), and for the heart and vascular development (Hallaq et al, 2004), but the formation of endothelial and hematopoietic lineages takes places. During ESC differentiation in vitro, Hex is expressed in the BL-CFCs and acts as a negative regulator of the hemangioblast and its differentiation into definitive hematopoietic and endothelial cells (Nakagawa et al, 2003;Kubo et al, 2005).…”