Homeobox

Summary

A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism. Homeoboxes are found within genes that are involved in the regulation of patterns of anatomical development (morphogenesis) in animals, fungi, plants, and numerous single cell eukaryotes. Homeobox genes encode homeodomain protein products that are transcription factors sharing a characteristic protein fold structure that binds DNA to regulate expression of target genes. Homeodomain proteins regulate gene expression and cell differentiation during early embryonic development, thus mutations in homeobox genes can cause developmental disorders. Homeosis is a term coined by William Bateson to describe the outright replacement of a discrete body part with another body part, e.g. antennapedia—replacement of the antenn

Official source

https://en.wikipedia.org/wiki/Homeobox

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Elucidating the role of Hmx1 during mouse development

Linda Bapst

This thesis focuses on the study of H6 homeobox 1 (HMX1) gene, a homeobox-containing transcription factor involved in sensory organ and eye development and responsible for the oculo-auricular syndrome of Schorderet-Munier-Franceschetti. The purpose of my study is to better understand the mechanism and role of this transcription factor. My thesis is divided into three parts. The first part proposes a predictive promoter model approach to identify new HMX1 target gene. The second part concerns an animal model of Hmx1 mutation, the dumbo mouse model, and brings a new insight into lethal craniofacial defects. The third part concerns the characterization of the visual capacity of the dumbo mice and a description of a new pattern of vision-linked defects. In the first part we propose a predictive promoter model approach based on transcriptomic analysis of post-natal day 15 mouse retina from dumbo and wild type mouse. This method revealed that Sgcg, Tshz2 and Slc6a9 were Hmx1 targets in the mouse retina. Ptpro, Sema3f, and Epha6 belong to the retinal axon guidance pathway and play an important role in retinotopic mapping. Significant enrichment of HMX1 binding site confirmed this pathway and we validated the transcriptional activity of Hmx1 on Ptpro, Sema3f and Sgcg by Luciferase assay. In the second part of the project we investigate the dumbo mouse model, carrying a stop codon in Hmx1, and representing the first animal model for the oculo-auricular syndrome of Schorderet-Munier-Franceschetti. The homozygous Hmx1dmbo is a semi-lethal mutation and stillborns present severe craniofacial defects, including cleft palate, chest defect and bone hypoplasia of maxilla, zygomatic process, mandible and frontal. In the third part of the thesis we provide a complete description of the vision in dumbo mouse. Despite a normal retinal phenotype, the vision of this mouse is completely impaired. We demonstrate that this was caused by abnormal retinotopic mapping and optic nerve hypoplasia. In dumbo mice the retinal ganglion cells axon projections failed to target the visual output, namely the dorsal lateral geniculate nucleus and the superior colliculus, and present abnormal patterning.

EPFL2015

Krox-20 is a mouse zinc finger gene expressed in a segment-specific manner in the early central nervous system, which makes it a potential developmental control gene. In this report, we show that the Krox-20 protein binds in vitro to two specific DNA sites located upstream from the homeobox containing gene Hox-1.4. The nucleotide sequence recognized by Krox-20 is closely related to the Sp1 target sequence, which is consistent with the similarity existing between the zinc fingers of the two proteins. In co-transfection experiments in cultured cells, Krox-20 dramatically activates transcription from the herpes simplex virus thymidine kinase promoter when an oligomer of its binding site is present in cis close to the promoter. Analysis of mutated binding sites demonstrates that the level of activation by Krox-20 correlates with the affinity of the protein for the mutant sequence. These data indicate that Krox-20 constitutes a sequence-specific DNA-binding transcription factor. Parallel analysis of the expression of Krox-20 and Hox-1.4 in the neural tube by in situ hybridization revealed no overlap, arguing against direct interactions between these two genes. The possible involvement of Krox-20 in the regulation of the transcription of other homeobox genes is discussed in view of their respective patterns of expression.

1990

Homeobox genes and pattern formation in the vertebrate limb

Denis Duboule

The developing vertebrate limb is a powerful system to study genes potentially involved in pattern formation. Many such candidate genes encode transcription factors belonging to the class of the "homeodomain" proteins. In this short review, we discuss the possible functions of different subfamilies of homeobox genes. Genes belonging to the Hox family (related to the Drosophila homoeotic genes), such as the HOX-1, HOX-3, and HOX-4, complexes are probably among those encoding the patterning information. Their differential expression in the mesenchymal compartment is proposed to be responsible for the determination of the various axial elements. Other homeobox-containing genes are expressed in both the mesenchyme of the progress zone and the ectodermal ridge. These genes, Hox-7.1 and Hox-8.1, are related to the Drosophila msh gene and could be involved in epithelial-mesenchymal interactions linking the growth of the system to its patterning

1992

Elucidating the role of Hmx1 during mouse development

Linda Bapst

EPFL2015