NIH Reporter #5R35GM147273-06

A new animal model to elucidate mechanisms of gene regulation and embryonic patterning

This award funds research at Harvard University to study Hox genes in cephalopods to understand gene regulation and embryonic patterning, with implications for human developmental biology and disease.

Description

Hox genes serve as critical regulators of developmental processes. Disruption of their function during embryogenesis results in dramatic “homeotic” phenotypes where regions of the body are transformed from one identity to another. In humans, these disruptions can lead to malformation of the face, ears, limbs, and genitalia, as well as neural defects and cancer. In many animal genomes, the Hox genes are found in clusters: in vertebrates, these clusters are compact, while those of invertebrates are more loosely arranged or fragmented. While still poorly understood, the structure of the Hox cluster is hypothesized to be important in regulating their deployment. However, this is difficult to study in vertebrates as their genomes encode multiple Hox clusters that are the result of whole genome duplications. While invertebrates typically have a single, intact, but massively expanded Hox cluster, cephalopods have the largest Hox clusters yet described, with the squid Hox cluster being two orders of magnitude larger than those in humans. Conservation of the Hox cluster in cephalopods suggests that elements of the ancestral regulatory program are retained despite the dramatic increase in cluster size. Preliminary knockout data indicate that loss of a Hox gene results in the absence, rather than the transformation, of body regions, pointing to a different mode of action than in segmented animals. Understanding these differences will provide fundamental insights into the regulation of body plan transcription factors across species, including humans.

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