Signaling with Homeoprotein Transcription Factors in Development and Throughout Adulthood

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.

Increased Excitability and Reduced Excitatory Synaptic Input Into Fast-Spiking CA2 Interneurons After Enzymatic Attenuation of Extracellular Matrix

“…A recent study revealed a key role of Otx2 in maturation of PV+ GABA interneurons and the closure of the critical period of developmental plasticity in the visual cortex (Courtois et al, 2003 ; Beurdeley et al, 2012 ; Bernard and Prochiantz, 2016 ). Thus, PNN-assisted Otx2 internalization process may increase the perisomatic inhibition of PCs, leading to a shift in the E/I balance (Prochiantz, 2013 ). Although there are no data on the functional role of Otx2 specifically within the hippocampus, it is plausible to assume on basis of cortical data that attenuation of PNNs by ChABC, which reduces Otx2 uptake by FSIs and, thus, reopens the critical period of these neurons and changes the FSIs excitability and excitatory innervation.…”

The Physiology of Homeoprotein Transduction

“…But what was quite obvious to many is that organ shape and cell shape were likely to be achieved by overlapping mechanisms and that the cells had to share information concerning their respective positions in a morphogenetic field. As discussed in the first part of this review, the discovery of HP signaling functions takes its origin from our interest in cell morphogenesis and the intercellular exchange of positional information (221,260).…”

Inter-Cellular Transport of Ran GTPase

“…Interestingly, protein profiling studies have suggested Ran to be present in the exosomes secreted by many cell types [ 50 – 54 ]. However, the possibility that Ran gets distributed through TNTs / microvesicles or involving non-conventional secretion similar to that reported for a class of proteins such as homeoproteins [ 35 , 36 ], needs to be confirmed by future work.…”

“…The known methods of inter-cellular transfer of molecules/organelles involve microvesicles (exosomes and shedding vesicles) [ 27 – 29 ], TNTs [ 25 , 26 ] and non-conventional secretion and internalization [ 35 , 36 ]. It is possible that Ran GTPase might take any of the routes to travel between cells.…”

“…Interestingly, TNTs and microvesicles are shown to function in immune cell signalling and cancer progression [ 28 , 29 , 32 – 34 ]. Additionally, a class of proteins, including homeoproteins, is shown to exhibit inter-cellular movement through a mechanism involving non-conventional secretion and internalization [ 35 , 36 ].…”