J. Dev. Biol.2016, 4(2), 19; doi:10.3390/jdb4020019 - published 25 May 2016 Show/Hide Abstract
Abstract: The silk gland of the silkworm Bombyx mori is a long tubular organ that is divided into several subparts along its anteroposterior (AP) axis. As a trait of terminal differentiation of the silk gland, several silk protein genes are expressed with unique regional specificities. Most of the Hox and some of the homeobox genes are also expressed in the differentiated silk gland with regional specificities. The expression patterns of Hox genes in the silk gland roughly correspond to those in embryogenesis showing “colinearity”. The central Hox class protein Antennapedia (Antp) directly regulates the expression of several middle silk gland–specific silk genes, whereas the Lin-1/Isl-1/Mec3 (LIM)-homeodomain transcriptional factor Arrowhead (Awh) regulates the expression of posterior silk gland–specific genes for silk fiber proteins. We summarize our results and discuss the usefulness of the silk gland of Bombyx mori for analyzing the function of Hox genes. Further analyses of the regulatory mechanisms underlying the region-specific expression of silk genes will provide novel insights into the molecular bases for target-gene selection and regulation by Hox and homeodomain proteins.
J. Dev. Biol.2016, 4(2), 17; doi:10.3390/jdb4020017 - published 19 May 2016 Show/Hide Abstract
Abstract: At a cellular level, nutrients are sensed by the mechanistic Target of Rapamycin (mTOR). The response of cells to hypoxia is regulated via action of the oxygen sensor Hypoxia-Inducible Factor 1 (HIF-1). During development, injury and disease, tissues might face conditions of both low nutrient supply and low oxygen, yet it is not clear how cells adapt to both nutrient restriction and hypoxia, or how mTOR and HIF-1 interact in such conditions. Here we explore this question in vivo with respect to cell proliferation using the ciliary marginal zone (CMZ) of Xenopus. We found that both nutrient-deprivation and hypoxia cause retinal progenitors to decrease their proliferation, yet when nutrient-deprived progenitors are exposed to hypoxia there is an unexpected rise in cell proliferation. This increase, mediated by HIF-1 signalling, is dependent on glutaminolysis and reactivation of the mTOR pathway. We discuss how these findings in non-transformed tissue may also shed light on the ability of cancer cells in poorly vascularised solid tumours to proliferate.
J. Dev. Biol.2016, 4(2), 18; doi:10.3390/jdb4020018 - published 19 May 2016 Show/Hide Abstract
Abstract: In gnathostomes, limb buds arise from the lateral plate mesoderm at discrete positions along the body axis. Specification of these limb-forming fields can be subdivided into several steps. The lateral plate mesoderm is regionalized into the anterior lateral plate mesoderm (ALPM; cardiac mesoderm) and the posterior lateral plate mesoderm (PLPM). Subsequently, Hox genes appear in a nested fashion in the PLPM and provide positional information along the body axis. The lateral plate mesoderm then splits into the somatic and splanchnic layers. In the somatic layer of the PLPM, the expression of limb initiation genes appears in the limb-forming region, leading to limb bud initiation. Furthermore, past and current work in limbless amphioxus and lampreys suggests that evolutionary changes in developmental programs occurred during the acquisition of paired fins during vertebrate evolution. This review presents these recent advances and discusses the mechanisms of limb field specification during development and evolution, with a focus on the role of Hox genes in this process.
J. Dev. Biol.2016, 4(2), 16; doi:10.3390/jdb4020016 - published 9 May 2016 Show/Hide Abstract
Abstract: Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo? Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind? Third, what determines whether a Hox factor will activate or repress a specific target gene? Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE).
J. Dev. Biol.2016, 4(2), 15; doi:10.3390/jdb4020015 - published 26 March 2016 Show/Hide Abstract
Abstract: Hoxa2 is an evolutionarily conserved developmental regulatory gene that functions to specify rhombomere (r) and pharyngeal arch (PA) identities throughout the Osteichthyes. Japanese medaka (Oryzias latipes) hoxa2a, like orthologous Hoxa2 genes from other osteichthyans, is expressed during embryogenesis in r2–7 and PA2-7, whereas the paralogous medaka pseudogene, ψhoxa2b, is expressed in noncanonical Hoxa2 domains, including the pectoral fin buds. To understand the evolution of cis-regulatory element (CRE) control of gene expression, we conducted eGFP reporter gene expression studies with extensive functional mapping of several conserved CREs upstream of medaka hoxa2a and ψhoxa2b in transient and stable-line transgenic medaka embryos. The CREs tested were previously shown to contribute to directing mouse Hoxa2 gene expression in r3, r5, and PA2-4. Our results reveal the presence of sequence elements embedded in the medaka hoxa2a and ψhoxa2b upstream enhancer regions (UERs) that mediate expression in r4 and the PAs (hoxa2a r4/CNCC element) or in r3–7 and the PAs ψhoxa2b r3–7/CNCC element), respectively. Further, these elements were shown to be highly conserved among osteichthyans, which suggests that the r4 specifying element embedded in the UER of Hoxa2 is a deeply rooted rhombomere specifying element and the activity of this element has been modified by the evolution of flanking sequences that redirect its activity to alternative developmental compartments.
J. Dev. Biol.2016, 4(2), 13; doi:10.3390/jdb4020013 - published 25 March 2016 Show/Hide Abstract
Abstract: A critical position in the developmental hierarchy is occupied by the Hox genes, which encode transcription factors. Hox genes are crucial in specifying regional identity along the embryonic axes and in regulating morphogenesis. In mouse, targeted mutations of Hox genes cause skeletal transformations and organ defects that can impair viability. Here, we present the current knowledge about the Hoxa5 gene, a paradigm for the function and the regulation of Hox genes. The phenotypic survey of Hoxa5−/− mice has unveiled its critical role in the regional specification of the skeleton and in organogenesis. Most Hoxa5−/− mice die at birth from respiratory distress due to tracheal and lung dysmorphogenesis and impaired diaphragm innervation. The severity of the phenotype establishes that Hoxa5 plays a predominant role in lung organogenesis versus other Hox genes. Hoxa5 also governs digestive tract morphogenesis, thyroid and mammary glands development, and ovary homeostasis. Deregulated Hoxa5 expression is reported in cancers, indicating Hoxa5 involvement in tumor predisposition and progression. The dynamic Hoxa5 expression profile is under the transcriptional control of multiple cis-acting sequences and trans-acting regulators. It is also modulated by epigenetic mechanisms, implicating chromatin modifications and microRNAs. Finally, lncRNAs originating from alternative splicing and distal promoters encompass the Hoxa5 locus.