Mechanisms of developmental neurite pruning

Abstract

The precise wiring of the nervous system is a combined outcome of progressive and regressive events during development. Axon guidance and synapse formation intertwined with cell death and neurite pruning sculpt the mature circuitry. It is now well recognized that pruning of dendrites and axons as means to refine neuronal networks, is a wide spread phenomena required for the normal development of vertebrate and invertebrate nervous systems. Here we will review the arising principles of cellular and molecular mechanisms of neurite pruning. We will discuss these principles in light of studies in multiple neuronal systems, and speculate on potential explanations for the emergence of neurite pruning as a mechanism to sculpt the nervous system.

Fig. 1

Early observations of neuronal remodeling. A drawing by Santiago Ramon y Cajal highlighting process elimination during granule cell development. As development proceeds (a–g), granule cells initially form exuberant dendrites (d) that are later eliminated (resorbed, in Ramon y Cajal’s own words; e) and undergo regrowth and maturation (f, g). Figure taken from [12], with permission from Oxford University Press (UK)

Fig. 2

Pruning by local fragmentation. Localized neurite fragmentation is a widespread mechanism to eliminate unwanted connections. a Drosophila MB γ neurons eliminate dendrites and some parts of their axons in a stereotypic manner via localized fragmentation. While the dorsal (D) and medial (M) axonal branches as well as the dendrite (Den) undergo pruning, the peduncular axon (P) remains intact. b Dendrites of larval fly sensory da neurons are eliminated via severing following by localized fragmentation. The axons of these da neurons remain intact. c Murine retinal ganglion cell (RGCs) axons projecting to the superior colliculus (SC) overshoot their target zone (TZ) and then eliminate unnecessary connections via fragmentation. d Murine Layer 5 (L5) cortical neurons from the motor and visual regions initially send out identical projections to the spinal cord and visual areas including the superior colliculus (SC). Later, they undergo selective axon elimination via localized fragmentation (dashed red line) such that L5 cortical neurons from the visual area retain only their visual connections and vice versa. The schematics depicting RGCs and L5 cortical neurons were modified with permission from Luo and O’Leary [7]

Fig. 3

Pruning by local retraction. Hippocampal granule cells in the dentate gyrus (DG) initially extend two axonal bundles, the main and infrapyramidal bundles (MB and IPB, respectively), that innervate the CA3 pyramidal cells. Subsequently the IPB is eliminated via apparent retraction while the MB remains intact

Fig. 4

Pruning by axosome shedding. Motor axons compete for target innervation (muscle) during the formation of the neuromuscular junction (NMJ). The losing synapse is pruned by axosome shedding while the winning synapse expands to occupy the full junction

Fig. 5

Pruned neurites are cleared via engulfment by neighboring cells. a Fragmented Drosophila MB γ axons are engulfed and cleared by astrocytes (green). The role or subtype of other glial cells in the vicinity of the MB (purple) is currently not known. b Fragmented Drosophila dendrites of da neurons are engulfed predominantly by epidermal cells (yellow) and to a lesser extent also by plasmatocytes (purple). c Remnants of mouse motoneuron axosomes are engulfed by neighboring Schwann cells

Fig. 6

Pruning receptors and signaling pathways. A schematic representation of molecules that are important for neuronal remodeling. Axon guidance receptors (Plexin-A3, Neuropillin-2, and eprin-B3), receptors of the TGF-β family, and death receptors (p75, DR6) induce pruning through diverse signaling pathways. These include the apoptotic machinery, actin regulators and transcription factors