Lysosomal Hydrolase Cathepsin D Non-proteolytically Modulates Dendritic Morphology in Drosophila

The main lysosomal protease cathepsin D(cathD)is essential for maintaining tissue homeostasis via its degradative function,and its loss leads to ceroid accumulation in the mammalian nervous system,which results in progressive neurodegeneration.Increasing evidence implies non-proteolytic roles of cathD in regulating various biological processes such as apoptosis,cell proliferation,and migration.Along these lines,we here showed that cathD is required for modulating dendritic architecture in the nervous system independent of its traditional degradative function.Upon cathD depletion,class I and class III arborization(da)neurons in Drosophila larvae exhibited aberrant dendritic morphology,including overbranching,aberrant turning,and elongation defects.Reintroduction of wild-type cathD or its proteolyticallyinactive mutant dramatically abolished these morphological defects.Moreover,cathD knockdown also led to dendritic defects in the adult mushroom bodies,suggesting that cathD-mediated processes are required in both the peripheral and central nervous systems.Taken together,our results demonstrate a critical role of cathD in shaping dendritic architecture independent of its proteolytic function.

Regulatory mechanisms underlying the differential growth of dendrites and axons

A typical neuron is comprised of an information input compartment, or the dendrites, and an output compartment, known as the axon. These two compartments are the structural basis for functional neural circuits, However, little is known about how dendritic and axonal growth are differentially regulated. Recent studies have uncovered two distinct types of regulatory mechanisms that differentiate dendritic and axonal growth： dedicated mechanisms and bimodal mechanisms. Dedicated mechanisms regulate either dendrite- specific or axon-specific growth; in contrast, bimodal mechanisms direct dendritic and axonal development in opposite manners. Here, we review the dedicated and bimodal regulators identified by recent Drosophila and mammalian studies. The knowledge of these underlying molecular mechanisms not only expands our understanding about how neural circuits are wired, but also provides insights that will aid in the rational design of therapies for neurological diseases.

FOXG1 Directly Suppresses Wnt5a During the Development of the Hippocampus

The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis.However,the mechanism underlying the regulation of Wnt5a remains unclear.Here,through conditional disruption of Foxg1 in hippocampal progenitors and postmitotic neurons achieved by crossing Foxg1~(fl/fl)with Emx1-Cre and Nex-Cre,respectively,we found that Wnt5a rather than Wnt3a/Wnt2b was markedly upregulated.Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus.We further demonstrated that FOXG1 directly repressed Wnt5a by binding to its promoter and one enhancer site.These results expand our knowledge of the interaction between Foxg1 and Wnt signaling and help elucidate the mechanisms underlying hippocampal development.