Precursor types predict the stability of neuronal branches

Branches are critical for neuron function, generating the morphological complexity required for functional networks. They emerge from different, well-described, cytoskeletal precursor structures that elongate to branches. While branches are thought to be maintained by shared cytoskeletal regulators, our data from mouse hippocampal neurons indicate that the precursor structures trigger alternative branch maintenance mechanisms with differing stabilities. While branches originating from lamellipodia or growth cone splitting events collapse soon after formation, branches emerging from filopodia persist. Furthermore, compared to other developing neurites, axons stabilise all branches and preferentially initiate branches from filopodia. These differences explain the decreased stability of branches we observe in neurons lacking the plasma membrane protein phospholipid phosphatase related protein 3 (PLPPR3/PRG2). Rather than altering branch stability directly, PLPPR3 boosts a ‘filopodia branch program’ on axons, thereby indirectly initiating more long-lived branches. We propose that studies on branching should distinguish overall stabilising effects from effects on precursor types, ideally using multifactorial statistical models as exemplified in this study.