Review
The topological role of homeoproteins in the developing central nervous system

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Homeogenes encode homeoprotein transcription factors that have fundamental roles in development. They are key players in genetic networks that lay out the body plan and also determine morphology and physiology at the cellular and multicellular level. However, homeoproteins share activities that extend beyond transcription, including translation regulation and signalling. For example, homeoproteins participate in the definition of territories in the neuroepithelium and also have a function in axonal guidance. Based on these examples, we propose that homeoproteins are not only morphogenetic transcription factors, but also morphogens themselves.

Introduction

Harmonious development of multicellular organisms requires the differentiation of cells and organs in accordance with position and time. As a result, systems have evolved for cells to read their own position, and that of their neighbours, and to make appropriate decisions in terms of lineage, morphology and organogenesis. In this context, the discovery of genes in the fly that coordinate the development of appendages in relation to their position along the body axis can be regarded as seminal [1]. This discovery led to the description of homeogenes, an important class of developmental genes that encode transcription factors termed homeoproteins. However, it also opened up a vast area of research aimed at understanding how genomic mutations affect shape, lineage and physiology at the cellular and multicellular levels. This is why, since the late 1980s, the elucidation of genetic networks involving homeogenes has been given a high priority by many developmental biologists. Great progress has been made in identifying genes upstream and downstream of homeogenes as key players in translating genetic instructions into morphological and physiological traits. In this context, positional information is of primary importance for the development and function of the nervous system. For example, assembling the billions of neurons – not to mention other cell types – and synapses in a vertebrate brain is clearly an extraordinary achievement. Consequently, here, we discuss the topological role of homeogenes in the developing central nervous system, with particular focus on axonal guidance and on the positioning of boundaries within the neuroepithelium. We further discuss the mechanisms involved and show that homeoproteins can act not only as transcription factors, but also as direct signalling proteins.

Section snippets

The biochemical functions of homeoproteins

Homeoproteins are expressed at all developmental stages and in the adult. Although adult functions have not been studied extensively, one can distinguish between activities associated with adult development – for example, the control of adult stem cell proliferation and division [2] – and activities that would not have been easily predicted, such as the role of engrailed (a collective term for homeoproteins engrailed-1 and engrailed-2) in the survival of adult midbrain dopaminergic neurons [3].

Forming boundaries with homeoproteins

The demonstration that the combinatorial expression of homeoproteins regulates the formation of abutting territories (i.e. rhombomeres) in the developing nervous system can be considered as one of the most salient findings in recent developmental biology 4, 18. Indeed, it is important not only from developmental and physiological perspectives, but also in terms of evolution because brains differ between species not only by the general size of the neuroepithelium, but also by the respective

Axonal guidance: the retinotectal model

On the basis of experiments associating experimental embryology and behaviour studies, Sperry postulated that the retinal map projects in an orderly fashion onto the tectum, in such a way that the topography of visual objects analyzed by the retinal ganglion cells (RGCs) would be preserved at the level of higher brain centres. Going one step further, he proposed that this topographic preservation was facilitated by the ability of individual growth cones, emanating from RGCs in various positions

Signalling with homeoproteins: the engrailed example

Given the plethora of guidance factors, one might question the need to add a homeoprotein to the list. In the remainder of this review, we hope to convince the reader that this addition might simplify our views on axonal guidance. The arguments supporting an important signalling function for engrailed in axonal guidance are logical, biochemical and functional in nature. Logical because the intercellular passage of factors endowed with positional information is certainly the most parsimonious

Are homeoproteins morphogens?

We now look at these results from an evolutionary standpoint that, although speculative, enables us to substantiate further the idea that homeoproteins are not only morphogenetic transcription factors regulating morphogen synthesis, but also actual morphogens themselves. Homeoprotein intercellular passage has also been demonstrated in metaphytes, and some of the mechanisms identified in animal models also work for plant homeoproteins 55, 56. This suggests that homeogenes were present before the

Concluding remarks

In the early 1990s, our group discovered the uncanny ability of homeodomains and homeoproteins to translocate across biological membranes. This led to the deciphering of unconventional mechanisms for the secretion and internalization of many members of this family of transcription factors. However, developmental functions of this phenomenon, as described here, have emerged only recently. In light of these functions, we conclude with three remarks that we see as essential. First, homeoprotein

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    The three first co-authors participated equally in the review.

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