Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules

Abstract

SummaryTo understand the functions of SPG6, mutated in the neurodegenerative disease hereditary spastic paraplegia, and of ichthyin, mutated in autosomal recessive congenital ichthyosis, we have studied their Drosophila ortholog, spichthyin (Spict). Spict is found on early endosomes. Loss of Spict leads to upregulation of BMP signaling and expansion of the neuromuscular junction. BMP signaling is also necessary for a normal microtubule cytoskeleton and axonal transport; analysis of loss and gain-of-function phenotypes suggests that Spict antagonizes this function of BMP signaling. Spict interacts with BMP receptors and promotes their internalization from the plasma membrane, suggesting that it inhibits BMP signaling by regulating BMP receptor traffic. This is the first demonstration of a role for an SPG protein or ichthyin family member in a specific signaling pathway, and suggests disease mechanisms for hereditary spastic paraplegia that involve dependence of the microtubule cytoskeleton on BMP signaling.

dCIP4 (Drosophila Cdc42-Interacting Protein 4) Restrains Synaptic Growth by Inhibiting the Secretion of the Retrograde Glass Bottom Boat Signal

“…At the Drosophila NMJ, the BMP ligand Gbb, secreted from postsynaptic muscles, acts as a critical retrograde signal that promotes the structural growth of presynaptic terminals. Previous studies have demonstrated that endocytic regulation of BMP receptors is a presynaptic mechanism to restrain Gbb-induced synaptic growth (Wang et al, 2007;O'ConnorGiles et al, 2008). Here, we present data demonstrating that inhibition of Gbb secretion by the postsynaptic dCIP4 pathway also contributes to fine regulation of retrograde BMP signaling and synaptic growth.…”

“…Mutations in various endocytic genes, including dap160/intersectin, spin, and spichthyin (spict), cause synaptic overgrowth (Sweeney and Davis, 2002;Marie et al, 2004;Wang et al, 2007), and this phenotype is suppressed by additional mutations that disrupt BMP signaling (Sweeney and Davis, 2002;Wang et al, 2007;O'Connor-Giles et al, 2008), suggesting that endocytosis contribute negatively to retrograde BMP signaling. However, it is not known whether retrograde BMP signaling is also regulated at the level of Gbb secretion.…”

Molecular identification of ancient and modern mammalian magnesium transporters

“…There is evidence that human ichthyin and its Drosophila ortholog spichthyin are also localized to early recycling endosomes and the plasma membrane (20,169). The peripheral localization of the NIPA proteins suggests that they might play a role, such as mediation of Mg 2ϩ transport, at the surface membrane.…”

“…There is some evidence that these changes may depend on the integrity of the microtubule cytoskeleton. Using a Drosophila fly model, Wang et al (169) reported that spichthyin loss of function results in dysregulation of bone morphogenic protein signaling and the maintenance of axonal microtubules. If the basis for these observations is not Mg 2ϩ transport, then it is interesting to speculate that NIPA1 and ichthyin might have other functions.…”

Multifunctional Role of Protein Kinase C in Regulating the Formation and Maturation of Specific Synapses

“…Several membrane or secretory proteins and their receptors are candidate molecules that might contribute to the formation of specific synapses (Wells et al, 1999;Tao and Poo, 2001;Lee et al, 2003;Blagburn and Bacon, 2004;Graf et al, 2004;McCabe et al, 2004;Shen et al, 2004;Boucard et al, 2005: Chih et al, 2005Christopherson et al, 2005;Sara et al, 2005;Wang et al, 2007). However, the orchestration of the signaling mechanisms mediating target selection, branching, synapse formation, and maintenance is not well understood.…”