Hox genes in the lung.

Abstract

Hox genes are a specific subgroup of homeobox containing genes that are characterized by their structural and functional homology to homeotic genes of the fruit fly Drosophila (1). These genes play important roles in pattern formation along the anterior-posterior axis in the developing embryo in both invertebrates and vertebrates (2). The proteins encoded by Hox genes contain the DNA-binding homeodomain (3), and are therefore believed to act as transcription factors that regulate the expression of other genes during morphogenesis (4, 5). More than 100 of other genes have been identified in mammals that encode homeodomain proteins (6, 7) of which the Hox genes are the best characterized. A growing number of animals with genetically induced aberrant Hox gene expression is providing insight into the crucial function of Hox genes in axial patterning; it is also becoming clear that Hox genes are important in the development of internal organs and the differentiation of tissues.The development of the lung starts out from protrusions of the primitive gut, the lung buds (8). Elongation and branching then leads to the formation of the trachea and bronchi and progressive branching elaborates the distal alveoli (9). The proximal-distal orientation of these distinct structures suggests that they could be specified by mechanisms paralleling those that govern anterior-posterior (rostral-caudal) axial specification. The inner surface of the lung is derived from endodermal cells that differentiate into epithelial cells under the influence of the surrounding mesenchymal cells which are of mesodermal origin (reviewed in (10). It is believed that interactions with the mesenchyme are important for epithelial cell differentiation and function. In short, lung development is characterized by two phases, the early specification of the proximal-distal axis and later events of tissue differentiation. As I will present here, there is increasing evidence that Hox genes are involved both in regional specification and cell differentiation in lung development. The genomic organization of vertebrate Hox genesis characterized by their arrangement in chromosomal clusters (11). Figure 1 shows schematically that highly similar genes (paralogs) occupy corresponding positions on different clusters. Intriguingly, the position of genes within a cluster is correlated to their order of expression along the anterior-posterior (rostral-caudal) axis (12). In addition, the genes located towards the 5′ end of the clusters have been shown to be expressed in developing limbs in anterior-posterior (thumb-pinkie) and proximal-distal direction (13). The overlapping but distinct expression patterns have been taken to suggest that a combinatorial code of Hox gene expression specifies the subsequent development of a given body region (14).

HOX gene clusters are hotspots of de novo methylation in CpG islands of human lung adenocarcinomas

“…It has been reported that a minority of the genes continue to be expressed in adult lung tissue (Tiberio et al, 1994;Kappen, 1996;Calvo et al, 2000;Golpon et al, 2001;Lechner et al, 2001). The HOXA5 gene product positively regulates the expression of the In order to increase PCR eciency and speci®city during ampli®cation, 1 M betaine (Henke et al, 1997) was added.…”

The Molecular Basis for Abnormal Human Lung Development

“…Important growth factors are sonic hedgehog (Shh) and fi broblast growth factors (FGFs), specifi cally FGF10 [6][7][8] . Important transcription factors are hepatocyte nuclear factor-3 ␤ (HNF-3 ␤ or Foxa2) [9,10] , Hox genes [11,12] , Gli genes [13][14][15] and thyroid transcription factor-1 (TTF-1 or Nkx2.1) [16,17] . Several of these regulatory factors are also implicated in esophagealtracheal separation as well as left-right asymmetry development, including Shh [18] , Gli [13] , Foxj1a [19] and Pitx-2 [20,21] .…”

Respiratory Adaptations to Lung Morphological Defects in Adult Mice Lacking Hoxa5 Gene Function

“…Furthermore, characterization of Hox mutants has revealed unforeseen postnatal phenotypes, indicating the large range of action of Hox genes throughout life (8 -10). In the mouse, Hox genes, predominantly from paralogous groups 2 to 6, are expressed in a distinct spatio-temporal fashion during lung ontogeny, thereby supporting their involvement in regional lung specification and function (11)(12)(13)(14). Loss-offunction mutations for several lung-expressed Hox genes have been generated, but the consequences on the respiratory tract development and function have been examined for only a handful of these Hox mutants.…”