Noelins in Neural Development

Abstract

The nervous system arises from embryonic tissues beginning with neural induction, when signals from the mesoderm induce the overlying ectoderm to form neural precursors. During neurogenesis, neurons are selected to differentiate from the induced neural precursors. Here, I describe the isolation and characterization of the Xenopus Noelins, a family of gene isoforms that may play roles in both of these processes. Noelin proteins are alternatively spliced isoforms and are all secreted proteins. Biochemically, Noelin-1 and Noelin-4 interact; moreover, Noelin-4 interacts with BMP-4, a molecule that is implicated in the process of neural induction. Noelin transcripts are detected beginning at late gastrulation stages. Later, transcripts are observed in post-mitotic neural tissues of the central and peripheral nervous systems, from the neural tube closure stage and continuing through swimming tadpole stage. In avian embryos, Noelins are expressed in the early neural plate and neural crest, and over-expression of Noelin-1 and-2 leads to excess and prolonged neural crest emigration from the cranial neural tube. The Xenopus Noelin homologs do not appear to affect neural crest induction or migration; however, Noelin-1 is shown to have a role in promoting neuronal differentiation in neural tissue. Furthermore, the secretion of Noelin-1 is important for its ability to induce certain neural markers to be expressed. Remarkably, Noelin-4 causes neural induction when over-expressed in naive tissue; in whole embryos, it causes expansion and ectopic production of neural tissue and cement gland by conversion of ectoderm. Noelins may also modulate each others' functions: Noelin-1 activity is increased in the presence of Noelin-4, and surprisingly, Noelin-4 is negatively affected by the presence of Noelin-1. Since Noelin-4 can act as a neural inducer and can interact with BMP-4, a model for this gene's activity is proposed for modulation of BMP signaling. The function of Noelin-1 in modulating Noelin-4 activity may be mediated through competition for binding to BMP proteins. I further show that Morpholino antisense oligonucleotides that target all four Noelin isoforms cause a severe neural phenotype: the forebrain, cement gland and cranial ganglia are severely reduced or missing in injected embryos. These results indicate that Noelin proteins may be essential for normal development of anterior neural tissues. Thus, Noelin isoforms represent novel secreted factors involved in nervous system development, from neural induction to neurogenesis.