Christof Nolte

Hox Genes and Segmentation of the Hindbrain and Axial Skeleton

Segmentation is an important process that is frequently used during development to segregate groups of cells with distinct features. Segmental compartments provide a mechanism for generating and organizing regional properties along an embryonic axis and within tissues. In vertebrates the development of two major systems, the hindbrain and the paraxial mesoderm, displays overt signs of compartmentalization and depends on the process of segmentation for their functional organization. The hindbrain plays a key role in regulating head development, and it is a complex coordination center for motor activity, breathing rhythms, and many unconscious functions. The paraxial mesoderm generates somites, which give rise to the axial skeleton. The cellular processes of segmentation in these two systems depend on ordered patterns of Hox gene expression as a mechanism for generating a combinatorial code that specifies unique identities of the segments and their derivatives. In this review, we compare and contrast the signaling inputs and transcriptional mechanisms by which Hox gene regulatory networks are established during segmentation in these two different systems.

Expression of Hox Genes in the Nervous System of Vertebrates

The vertebrate nervous system is a major site of Hox gene expression and function. Studies on the patterns of expression, regulation and function of the vertebrate Hox gene family have played a key role in aiding our understanding of the basic ground plan of the CNS and processes that control how unique regional character is established and maintained in this complex organ system. This chapter will document the nature of the ordered patterns of Hox expression and link them with their regulation and functional roles in the nervous system.

An atypical presentation of Tako-Tsubo cardiomyopathy

We present the case of a patient with Tako-Tsubo cardiomyopathy whose initial diagnosis, based on the location of shoulder and chest pain and electrocardiographic (ECG) changes, suggested that she was suffering from pericarditis. However, 24 h after admission, evolutionary changes of ECG and the echocardiogram performed suggested a Tako-Tsubo cardiomyopathy. In this context, we review the literature to discuss the clinical presentation and evolutionary ECG changes associated with Tako-Tsubo cardiomyopathy.

Hox Genes Expression

Hox genes code for homeodomain-containing transcription factors that pattern the rostral–caudal (R/C) axis during embryogenesis. Their differential expression along the R/C axis is tightly regulated in both neural and non-neural tissue, and is the result of diverse, and sometimes opposing, regulatory influences. Signaling pathways important for development, such as the retinoic acid and fibroblast growth factor pathways, in combination with developmentally regulated transcription factors initiate their expression. This is subsequently maintained and refined by their own gene products through auto- and cross-regulatory mechanisms. Posttranscriptional mechanisms further refine these patterns and boundaries, resulting in a pattern of Hox gene expression that is unique at different levels of the embryonic R/C axis and underlies their functional roles in specification and patterning of tissues.

Retinoid-Sensitive Epigenetic Regulation of the Hoxb Cluster Maintains Normal Hematopoiesis and Inhibits Leukemogenesis

Hox genes modulate the properties of hematopoietic stem cells (HSCs) and reacquired Hox expression in progenitors contributes to leukemogenesis. Here, our transcriptome and DNA methylome analyses revealed that Hoxb cluster and retinoid signaling genes are predominantly enriched in LT-HSCs, and this coordinate regulation of Hoxb expression is mediated by a retinoid-dependent cis-regulatory element, distal element RARE (DERARE). Deletion of the DERARE reduced Hoxb expression, resulting in changes to many downstream signaling pathways (e.g., non-canonical Wnt signaling) and loss of HSC self-renewal and reconstitution capacity. DNA methyltransferases mediate DNA methylation on the DERARE, leading to reduced Hoxb cluster expression. Acute myeloid leukemia patients with DNMT3A mutations exhibit DERARE hypomethylation, elevated HOXB expression, and adverse outcomes. CRISPR-Cas9-mediated specific DNA methylation at DERARE attenuated HOXB expression and alleviated leukemogenesis. Collectively, these findings demonstrate pivotal roles for retinoid signaling and the DERARE in maintaining HSCs and preventing leukemogenesis by coordinate regulation of Hoxb genes.

Hox Complex Analysis Through BAC Recombineering

BAC transgenesis in mice has proved to be useful in exploring the regulatory mechanisms and functions of the Hox complexes. The large constructs used may include most of the relevant components of the cis-regulatory landscape. Manipulations can be accomplished without compromising the integrity of the endogenous complex which reduces the likelihood of producing confounding phenotypic abnormalities. The development of recombineering tools has been critical in providing the means necessary to make many types of precise and varied manipulations of these large constructs. Here, we will discuss the methodologies necessary to manipulate Hox complex BACs, generation of transgenic animals bearing these constructs and the utilization of these resources to address fundamental aspects of Hox biology.