Signaling with Homeoprotein Transcription Factors in Development and Throughout Adulthood

A Prochiantz

doi:10.2174/1389202911314060009

Abstract

The concept of homeoprotein transduction as a novel signaling pathway has dramatically evolved since it was first proposed in 1991. It is now well established in several biological systems from plants to mammals. In this review, the different steps that have led to this unexpected observation are recalled and the developmental and physiological models that have allowed us (and a few others) to consolidate the original hypothesis are described. Because homeoprotein signaling is active in plants and animals it is proposed that it has predated the separation between animals and plants and is thus very ancient. This may explain why the basic phenomenon of homeoprotein transduction is so minimalist, requiring no specific receptors or transduction pathways beside those offered by mitochondria, organelles present in all eukaryotic cells. Indeed complexity has been added in the course of evolution and the conservation of homeoprotein transduction is discussed in the context of its synergy with bona fide signaling mechanism that may have added robustness to this primitive cell communication device. The same synergy possibly explains why homeoprotein signaling is important both in embryonic development and in adult functions fulfilled by signaling entities (e.g. growth factors) themselves active throughout development and in the adult. The cell biological mechanism of homeoprotein transfer is also discussed. Although it is clear that many questions are still in want of precise answers, it appears that the sequences responsible both for secretion and internalization are in the DNA-binding domain and very highly conserved among most homeoproteins. On this basis, it is proposed that this signaling pathway is likely to imply as many as 200 proteins that participate in a myriad of developmental and physiological pathways.

Highlights

The identification of a novel signaling pathway based on homeoprotein (HP) transduction finds its origin in the observation that neurons and astrocytes isolated from different brain regions maintain their regional properties
In a recent study we demonstrated that, in contrast with the posterior cross vein (PCV) which requires the cell autonomous expression of En for its development, anterior cross vein (ACV) formation requires the secretion of En by the Patch domain [27]
DPP signaling leads to the phosphorylation of Mother Against DPP (MAD) and we found that MAD is not phosphorylated in absence of extracellular En, that full DPP signaling requires En secretion [27]

Summary

Introduction

The identification of a novel signaling pathway based on homeoprotein (HP) transduction finds its origin in the observation that neurons and astrocytes (a class of non-neuronal cells) isolated from different brain regions maintain their regional properties. This is why we developed the singlechain antibody strategy based on the in vivo expression of a secreted antibody allowing one to neutralize the extracellular HP while leaving untouched its cell autonomous activities (Fig. 2). In a recent study we demonstrated that, in contrast with the posterior cross vein (PCV) which requires the cell autonomous expression of En for its development, ACV formation requires the secretion of En by the Patch domain [27].

Results

Conclusion