Eye-brain interactions in the development and maintenance of the Drosophila visual system

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1994.Includes bibliographical references.by Margaret L. Winberg.Ph.D

Plexin A Is a Neuronal Semaphorin Receptor that Controls Axon Guidance

AbstractThe Semaphorins comprise a large family of secreted and transmembrane proteins, some of which function as repellents during axon guidance. Semaphorins fall into seven subclasses. Neuropilins are neuronal receptors for class III Semaphorins. In the immune system, VESPR, a member of the Plexin family, is a receptor for a viral-encoded Semaphorin. Here, we identify two Drosophila Plexins, both of which are expressed in the developing nervous system. We present evidence that Plexin A is a neuronal receptor for class I Semaphorins (Sema 1a and Sema 1b) and show that Plexin A controls motor and CNS axon guidance. Plexins, which themselves contain complete Semaphorin domains, may be both the ancestors of classical Semaphorins and binding partners for Semaphorins

Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates

In Drosophila, plexin A is a functional receptor for semaphorin-1a. Here we show that the human plexin gene family comprises at least nine members in four subfamilies. Plexin-B1 is a receptor for the transmembrane semaphorin Sema4D (CD100), and plexin-C1 is a receptor for the GPI-anchored semaphorin Sema7A (Sema-K1). Secreted (class 3) semaphorins do not bind directly to plexins, but rather plexins associate with neuropilins, coreceptors for these semaphorins. Plexins are widely expressed: in neurons, the expression of a truncated plexin-A1 protein blocks axon repulsion by Sema3A. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. We conclude that plexins are receptors for multiple (and perhaps all) classes of semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion

Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment