The labial gene is required to terminate proliferation of identified neuroblasts in postembryonic development of the Drosophila brain

The developing brain of Drosophila has become a useful model for studying the molecular genetic mechanisms that give rise to the complex neuronal arrays that characterize higher brains in other animals including mammals. Brain development in Drosophila begins during embryogenesis and continues during a subsequent postembryonic phase. During embryogenesis, the Hox gene labial is expressed in the developing tritocerebrum, and labial loss-of-function has been shown to be associated with a loss of regional neuronal identity and severe patterning defects in this part of the brain. However nothing is known about the expression and function of labial, or any other Hox gene, during the postembryonic phase of brain development, when the majority of the neurons in the adult brain are generated. Here we report the first analysis of Hox gene action during postembryonic brain development in Drosophila. We show that labial is initially expressed in six larval brain neuroblasts, of which only four give rise to the labial expressing neuroblast lineages present in the late larval brain. Although MARCM-based clonal mutation of labial in these four neuroblast lineages does not result in an obvious phenotype, a striking and unexpected effect of clonal labial loss-of-function does occur during postembryonic brain development, namely the formation of two ectopic neuroblast lineages that are not present in wild-type brains. The same two ectopic neuroblast lineages are also observed following cell death blockage and, significantly, in this case the resulting ectopic lineages are Labial-positive. These findings imply that labial is required in two specific neuroblast lineages of the wildtype brain for the appropriate termination of proliferation through programmed cell death. Our analysis of labial function reveals a novel cell autonomous role of this Hox gene in shaping the lineage architecture of the brain during postembryonic development

Spatial expression of Hox cluster genes in the ontogeny of a sea urchin

The Hox cluster of the sea urchin Strongylocentrous purpuratus contains ten genes in a 500 kb span of the genome. Only two of these genes are expressed during embryogenesis, while all of eight genes tested are expressed during development of the adult body plan in the larval stage. We report the spatial expression during larval development of the five 'posterior' genes of the cluster: SpHox7, SpHox8, SpHox9/10, SpHox11/13a and SpHox11/13b. The five genes exhibit a dynamic, largely mesodermal program of expression. Only SpHox7 displays extensive expression within the pentameral rudiment itself. A spatially sequential and colinear arrangement of expression domains is found in the somatocoels, the paired posterior mesodermal structures that will become the adult perivisceral coeloms. No such sequential expression pattern is observed in endodermal, epidermal or neural tissues of either the larva or the presumptive juvenile sea urchin. The spatial expression patterns of the Hox genes illuminate the evolutionary process by which the pentameral echinoderm body plan emerged from a bilateral ancestor

The regulation of Hox gene expression during animal development

Hox genes encode a family of transcriptional regulators that elicit distinct developmental programmes along the head-to-tail axis of animals. The specific regional functions of individual Hox genes largely reflect their restricted expression patterns, the disruption of which can lead to developmental defects and disease. Here, we examine the spectrum of molecular mechanisms controlling Hox gene expression in model vertebrates and invertebrates and find that a diverse range of mechanisms, including nuclear dynamics, RNA processing, microRNA and translational regulation, all concur to control Hox gene outputs. We propose that this complex multi-tiered regulation might contribute to the robustness of Hox expression during development

Evolutionary transition between invertebrates and vertebrates via methylation reprogramming in embryogenesis

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Xu, X., Li, G., Li, C., Zhang, J., Wang, Q., Simmons, D. K., Chen, X., Wijesena, N., Zhu, W., Wang, Z., Wang, Z., Ju, B., Ci, W., Lu, X., Yu, D., Wang, Q., Aluru, N., Oliveri, P., Zhang, Y. E., Martindale, M. Q., & Liu, J. Evolutionary transition between invertebrates and vertebrates via methylation reprogramming in embryogenesis. National Science Review, 6(5), (2019):993-1003, doi:10.1093/nsr/nwz064.Major evolutionary transitions are enigmas, and the most notable enigma is between invertebrates and vertebrates, with numerous spectacular innovations. To search for the molecular connections involved, we asked whether global epigenetic changes may offer a clue by surveying the inheritance and reprogramming of parental DNA methylation across metazoans. We focused on gametes and early embryos, where the methylomes are known to evolve divergently between fish and mammals. Here, we find that methylome reprogramming during embryogenesis occurs neither in pre-bilaterians such as cnidarians nor in protostomes such as insects, but clearly presents in deuterostomes such as echinoderms and invertebrate chordates, and then becomes more evident in vertebrates. Functional association analysis suggests that DNA methylation reprogramming is associated with development, reproduction and adaptive immunity for vertebrates, but not for invertebrates. Interestingly, the single HOX cluster of invertebrates maintains unmethylated status in all stages examined. In contrast, the multiple HOX clusters show dramatic dynamics of DNA methylation during vertebrate embryogenesis. Notably, the methylation dynamics of HOX clusters are associated with their spatiotemporal expression in mammals. Our study reveals that DNA methylation reprogramming has evolved dramatically during animal evolution, especially after the evolutionary transitions from invertebrates to vertebrates, and then to mammals.This work was supported by the National Key Research and Development Program of China (2018YFC1003303), the Strategic Priority Research Program of the CAS (XDB13040200), the National Natural Science Foundation of China (91519306, 31425015), the Youth Innovation Promotion Association of the CAS and the Key Research Program of Frontier Sciences, CAS (QYZDY-SSW-SMC016)

Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis

The Hox family are master transcriptional regulators of developmental processes, including hematopoiesis. The Hox regulators, caudal homeobox factors (Cdx1-4), and Meis1, along with several individual Hox proteins, are implicated in stem cell expansion during embryonic development, with gene dosage playing a significant role in the overall function of the integrated Hox network. To investigate the role of this network in normal and aberrant, early hematopoiesis, we employed an in vitro embryonic stem cell differentiation system, which recapitulates mouse developmental hematopoiesis. Expression profiles of Hox, Pbx1, and Meis1 genes were quantified at distinct stages during the hematopoietic differentiation process and compared with the effects of expressing the leukemic oncogene Tel/PDGFR;2. During normal differentiation the Hoxa cluster, Pbx1 and Meis1 predominated, with a marked reduction in the majority of Hox genes (27/39) and Meis1 occurring during hematopoietic commitment. Only the posterior Hoxa cluster genes (a9, a10, a11, and a13) maintained or increased expression at the hematopoietic colony stage. Cdx4, Meis1, and a subset of Hox genes, including a7 and a9, were differentially expressed after short-term oncogenic (Tel/PDGFR;2) induction. Whereas Hoxa4-10, b1, b2, b4, and b9 were upregulated during oncogenic driven myelomonocytic differentiation. Heterodimers between Hoxa7/Hoxa9, Meis1, and Pbx have previously been implicated in regulating target genes involved in hematopoietic stem cell (HSC) expansion and leukemic progression. These results provide direct evidence that transcriptional flux through the Hox network occurs at very early stages during hematopoietic differentiation and validates embryonic stem cell models for gaining insights into the genetic regulation of normal and malignant hematopoiesis

Role of HOX Genes in Stem Cell Differentiation and Cancer.

HOX genes encode an evolutionarily conserved set of transcription factors that control how the phenotype of an organism becomes organized during development based on its genetic makeup. For example, in bilaterian-type animals, HOX genes are organized in gene clusters that encode anatomic segment identity, that is, whether the embryo will form with bilateral symmetry with a head (anterior), tail (posterior), back (dorsal), and belly (ventral). Although HOX genes are known to regulate stem cell (SC) differentiation and HOX genes are dysregulated in cancer, the mechanisms by which dysregulation of HOX genes in SCs causes cancer development is not fully understood. Therefore, the purpose of this manuscript was (i) to review the role of HOX genes in SC differentiation, particularly in embryonic, adult tissue-specific, and induced pluripotent SC, and (ii) to investigate how dysregulated HOX genes in SCs are responsible for the development of colorectal cancer (CRC) and acute myeloid leukemia (AML). We analyzed HOX gene expression in CRC and AML using information from The Cancer Genome Atlas study. Finally, we reviewed the literature on HOX genes and related therapeutics that might help us understand ways to develop SC-specific therapies that target aberrant HOX gene expression that contributes to cancer development

Homeobox genes in normal and abnormal vasculogenesis

Homeobox containing genes are a family of transcription factors regulating normal development and controlling primary cellular processes (cell identity, cell division and differentiation) recently enriched by the discovery of their interaction with miRNAs and ncRNAs. Class I human homeobox genes (HOX genes) are characterized by a unique genomic network organization: four compact chromosomal loci where 39 sequence corresponding genes can be aligned with each other in 13 antero-posterior paralogous groups. The cardiovascular system is the first mesoderm organ-system to be generated during embryonic development; subsequently it generates the blood and lymphatic vascular systems. Cardiovascular remodelling is involved through homeobox gene regulation and deregulation in adult physiology (menstrual cycle and wound healing) and pathology (atherosclerosis, arterial restenosis, tumour angiogenesis and lymphangiogenesis). Understanding the role played by homeobox genes in endothelial and smooth muscle cell phenotype determination will be crucial in identifying the molecular processes involved in vascular cell differentiation, as well as to support future therapeutic strategies. We report here on the current knowledge of the role played by homeobox genes in normal and abnormal vasculogenesis and postulate a common molecular mechanism accounting for the involvement of homeobox genes in the regulation of the nuclear export of specific transcripts potentially capable of generating endothelial phenotype modification involved in new vessel formation

Hindgut specification and cell-adhesion functions of Sphox11/13b in the endoderm of the sea urchin embryo

Sphox11/13b is one of the two hox genes of Strongylocentrotus purpuratus expressed in the embryo. Its dynamic pattern of expression begins during gastrulation, when the transcripts are transiently located in a ring of cells at the edge of the blastopore. After gastrulation, expression is restricted to the anus–hindgut region at the boundary between the ectoderm and the endoderm. The phenotype that results when translation of Sphox11/13b mRNA is knocked down by treatment with morpholino antisense oligonucleotides (MASO) suggests that this gene may be indirectly involved in cell adhesion functions as well as in the proper differentiation of the midgut–hindgut and midgut–foregut sphincters. The MASO experiments also reveal that Sphox11/13b negatively regulates several downstream endomesoderm genes. For some of these genes, Sphox11/13b function is required to restrict expression to the midgut by preventing ectopic expression in the hindgut. The evolutionary conservation of these functions indicates the general roles of posterior Hox genes in regulating cell-adhesion, as well as in spatial control of gene regulatory network subcircuits in the regionalizing gut