My favourite molecule. Thy‐1, the enigmatic extrovert on the neuronal surface

Abstract

Thy‐1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain¹, are anchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail^(2,3) (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development ⁽⁴⁾. These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy‐1 to the status of a favourite molecule. Indeed, few scientists readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works. Thy‐1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology⁽⁵⁾; it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs^(1–3); it has been pivotal in studies demonstrating that GPI‐anchored molecules are able to signal across the membrane they do not span^{(6, 7)}. Thy‐1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged. Our current work on Thy‐1 in the nervous system is, we believe, finally prizing this last secret into the open. It suggests that Thy‐1 on the neuronal surface interacts with one of the main glial types of adult brain, the astrocyte, to restrict axonal growth⁽⁸⁾. There is no current consensus that astrocytes do regulate such growth, and this is the wider question we are addressing from the perspective of Thy‐1. At issue also is how to progress from knowing the nature of a molecule to defining its function. This task has already been achieved with molecules which were harder to characterise than Thy‐1. The problem is a classic Catch 22 situation: Thy‐1 has been readily characterised because it is small and abundant it is ten times more abundant than any other surface glycoprotein on rat thymocytes⁽⁹⁾; but since there is so much of it, whatever it does it must do rather badly (or there would be no need to have so much of it!). Defining a function based on low activity or affinity is not trivial. Here I describe two aspects of work on Thy‐1. One is long completed ‐ the research which led to Thy‐1 being isolated and characterised ‐ and included because it demonstrates features which are still applicable to much research using a antibodies today. The other is our ongoing work on the nervous system, which is at that exciting early stage where hypotheses are formed, but the answers are still coming in.