Hoxful Monsters

A novel mechanism of Hox proteins was deciphered by the group of Brian Gebelein ,where in Hox protein Abdominal -A (abd-A) permits secretion of EGF in Peripheral nervous system(PNS) by promoting rhomboid expression and by competing out senseless.

Hox genes are known for their selector activity which sculpt the body plan along anterior posterior axis. Hox protein control patterning of body plan in almost all metazoans by regulating distinct cells, tissues, and organs. So understanding how Hox proteins function is utmost important for better understanding of development and evolution.

David Li-Kroeger et.al, looked at this problem of Hox functional mechanism by studying the cis-regulatory element of Rhomboid (Rho654). Expression of rhomboid in a subset of sensory cells stimulates EGF secretion to induce hepatocyte-like (oenocytes) cell development. This enhacer Rho654 recapitulates the expression of endogenous rhomboid protein perfectly ,which can seen expressed in subsets of sensory organ precursor cells in Abdominal segments A1-A7 ( absent in posterior A8-A9 and also in Thoracic segments ,which are functional domains of Abd-B and Antennapedia Hox proteins respectively).

Rho654 enhancer harbours the binding sites for HOX ,its co factors extradenticle (exd ) and Homothorax (hth) and senseless in slightly overlapping manner. Senseless is also a transcription factors encoding a Zinc finger ,plays a vital role in PNS development by acting as repressor by binding to DNA.

Authors show some very nice in vitro ( Gel shifts) and invivo ( studying the mutant enhancers in flies)
data to prove that Hox proteins compete out senseless from binding to enhancer in subsets of cells in abdomen. Hox protein abd-A gets all the required support from its cofactors in the form of exd and hth (with hth playing slighly major role) to prevent senseless from binding to Rho654 and there by promoting development of oenocytes.

Further proof that complex of Hox -exd-hth promotes rhomboid expression and hence oenocytes formation by preventing the repressor (senseless in this case) and not by acting as activator ,comes from mutations that disrupt both Sens and Hox binding to RhoA (Rho654 Sens/Hox binding sites mutated). This enhancer stains shows expression in the thorax and abdomen, revealing that Exd/Hth/Abd-A binding is not required to activate gene expression.

Thus, unlike other Hox target genes, Hox complexes on RhoA are permissive rather than instructive and stimulate Rho654 by preventing the binding of a transcriptional repressor.

Reference :

Li-Kroeger D, Witt LM, Grimes HL, Cook TA, Gebelein B.
Hox and senseless antagonism functions as a molecular switch to regulate EGF secretion in the Drosophila PNS.
Dev Cell. 2008 Aug;15(2):298-308.