Segmentation of the caudal hindbrain into rhombomeres (r) 4-7 is regulated by paralog group 1 (PG1) Hox proteins, but it is unclear how PG1 Hox proteins activate their target genes and how these genes subsequently interact to produce distinct rhombomeres. Our preliminary results indicate that Hoxb1b (a zebrafish PG1 Hox protein) forms repressive complexes with Pbx proteins and histone deacetylases (HDACs) and that Meis proteins are required to convert Pbx:Hoxb1b complexes into transcriptional activators. We have also demonstrated that Hoxb1b regulates the expression of several genes in r4 (e.g. hoxb1a) and r5/r6 (e.g. val, vhnf1), but it is unclear how these genes act and it is likely that additional hoxb1b target genes exist. We hypothesize that Meis proteins displace HDACs from Pbx:Hoxb1b complexes to activate transcription of a few target genes that in turn regulate a cascade of transcription factors required for formation of r4-r7.
Our first aim i s to delineate Hoxb1b-regulated pathways that control formation of r4-r6. In particular, we will establish in which order vhnf1, val and hoxb1a act and how their expression domains become refined. We will also explore the function of several novel genes we have identified in r5/r6.
Our second aim i s to determine the role of Meis and Pbx cofactors in modulation of Hoxb1b function. We will explore the mechanism whereby Meis proteins displace HDACs from Pbx and we will test whether Meis acts in a similar manner to displace HDACs during activation of Hoxb1b target genes in vivo. Our experiments are important for several reasons. First, the hindbrain gives rise to several essential structures - sensory ganglia and branchiomotor neurons, as well as bone, cartilage and muscle of the vertebrate head. The developing hindbrain is sensitive to disruptions by a variety of factors (e.g. environmental toxins, infectious agents and genetic conditions) that give rise to a range of birth defects - motor control problems such as ataxia, cognitive defects such as autism and craniofacial defects. In addition, Hox proteins and Hox cofactors regulate other aspects of neural development (e.g. dorsoventral patterning of the neural tube), and other aspects of embryogenesis (e.g. hematopoiesis). hox, meis and pbx genes are also proto-oncogenes involved in leukemia. A better understanding of Hox function will therefore be applicable to a broad set of biological processes and human disease conditions. The embryonic hindbrain gives rise to many essential structures - sensory ganglia and branchiomotor neurons of the nervous system, as well as bone, cartilage and muscle of the head. The developing hindbrain is sensitive to disruptions by a variety of factors (e.g. environmental toxins, infectious agents and genetic conditions) that give rise to a range of birth defects - motor control problems such as ataxia, cognitive defects such as autism and craniofacial defects. In addition, the genes studied in this proposal regulate other aspects of neural development (e.g. dorsoventral patterning of the neural tube), and other aspects of embryogenesis (e.g. hematopoiesis). These genes are also proto-oncogenes involved in leukemia. The results from our proposed experiments will therefore be applicable to a broad set of biological processes and human disease conditions.
Showing the most recent 10 out of 26 publications
