Hereditary spastic paraplegia (HSP) is characterized by weakness and spasticity of the lower limbs, owing to degeneration of corticospinal axons. The most common form is due to heterozygous mutations in the SPG4 gene, encoding spastin, a microtubule (MT)‐severing protein. Here, we show that neurite growth in immortalized and primary neurons responds in pleiotropic ways to changes in spastin levels. Spastin depletion alters the development of primary hippocampal neurons leading to abnormal neuron morphology, dystrophic neurites, and axonal growth defects. By live imaging with End‐Binding Protein 3‐Fluorescent Green Protein (EB3‐GFP), a MT plus‐end tracking protein, we ascertained that the assembly rate of MTs is reduced when spastin is down‐regulated. Spastin over‐expression at high levels strongly suppresses neurite maintenance, while slight spastin up‐regulation using an endogenous promoter enhances neurite branching and elongation. Spastin severing activity is exerted preferentially on stable acetylated and detyrosinated MTs. We further show that SPG4 nonsense or splice site mutations found in hereditary spastic paraplegia patients result in reduced spastin levels, supporting haploinsufficiency as the molecular cause of the disease. Our study reveals that SPG4 is a dosage‐sensitive gene, and broadens the understanding of the role of spastin in neurite growth and MT dynamics.
Background: Anosmin-1, the protein implicated in the X-linked Kallmann's syndrome, plays a role in axon outgrowth and branching but also in epithelial morphogenesis. The molecular mechanism of its action is, however, widely unknown. Anosmin-1 is an extracellular protein which contains a cysteine-rich region, a whey acidic protein (WAP) domain homologous to some serine protease inhibitors, and four fibronectin-like type III (FnIII) repeats. Drosophila melanogaster Kal-1 (DmKal-1) has the same protein structure with minor differences, the most important of which is the presence of only two FnIII repeats and a C-terminal region showing a low similarity with the third and the fourth human FnIII repeats. We present a structure-function analysis of the different DmKal-1 domains, including a predicted heparan-sulfate binding site.
The olfactory system provides a unique model for developmental neurobiology. Precise targeting of axonal projections from sensory neurons located in the olfactory epithelium to specific neurons in the olfactory bulb establishes a highly refined spatial sensory map. Distinctively, this process is not restricted to embryonic stages, but continues during the entire life of mammals. A number of secreted and membrane molecules have been implicated in guidance and targeting of olfactory sensory neurons. Here we describe olfactorin, the protein product of the mouse Umodl1 gene, as a potential new element in this process. Olfactorin is a secreted modular protein containing several domains typically present in extracellular matrix proteins (EMI, WAP, FNIII, Ca2+ -binding EGF-like, SEA and ZP domains). By in situ hybridization we find that during embryonic development expression of the Umodl1 gene is detectable only in the olfactory epithelium and vomeronasal organ starting at embryonic day 16.5. At this stage, Umodl1 expression within the olfactory epithelium is punctate, and is restricted to only some of the sensory neurons. At birth and postnatally, expression in these organs continues and involves more neurons. Kallmann syndrome is a genetic disease in which olfactory axons fail to connect to target neurons in the bulb. We tested whether olfactorin might be responsible for an autosomal form of this disease and show that this is not the case. However, based on its domain composition and on the expression in olfactory neurons we suggest that olfactorin may play a role in correct olfactory axon navigation to the brain.
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