National Institute of General Medical Sciences 7R35GM147273-05

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

This award funds research to develop a new animal model to study gene regulation and embryonic patterning, focusing on the unique Hox gene clusters in cephalopods to gain insights into developmental biology and embryogenesis.

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 complement of Hox genes, many invertebrate Hox clusters are disrupted, including those found in the classic invertebrate model systems like flies and nematodes. To address this deficit, resources and tools for studying cephalopod molluscs (squid and octopus), including chromosome-scale genome assemblies, extensive transcriptomics, and tools for gene manipulation, have been developed. These studies have revealed that cephalopods have a single, intact, but massively expanded Hox cluster, which is the largest described to date—two orders of magnitude larger than in humans. Despite the dramatic increase in cluster size, cephalopod Hox genes exhibit canonical, collinear nested domains of expression, suggesting retention of ancestral regulatory elements. Knockout data indicate that loss of a Hox gene results in the absence, rather than transformation, of body regions, suggesting a different mode of action than in segmented animals. Understanding the regulation of these body plan transcription factors across diverse species, including humans, will provide fundamental insights into embryogenesis and developmental biology.

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