Abstract
Formation of long-range axons occurs over multiple stages of morphological maturation. However, the intrinsic transcriptional mechanisms that temporally control different stages of axon projection development are unknown. Here, we addressed this question by studying the formation of mouse serotonin (5-HT) axons, the exemplar of long-range profusely arborized axon architectures. We report that LIM homeodomain factor 1b (Lmx1b)-deficient 5-HT neurons fail to generate axonal projections to the forebrain and spinal cord. Stage-specific targeting demonstrates that Lmx1b is required at successive stages to control 5-HT axon primary outgrowth, selective routing, and terminal arborization. We show a Lmx1b→Pet1 regulatory cascade is temporally required for 5-HT arborization and upregulation of the 5-HT axon arborization gene, Protocadherin-alphac2, during postnatal development of forebrain 5-HT axons. Our findings identify a temporal regulatory mechanism in which a single continuously expressed transcription factor functions at successive stages to orchestrate the progressive development of long-range axon architectures enabling expansive neuromodulation.
Highlights
Generated neurons dramatically transform their morphology to establish mature circuit connectivity
TdTomato+ axon distribution in control brains was highly concordant with 5-HT axon projection patterns determined more recently using a mouse line in which GFP was knocked into the Tph2 coding region, validating our surrogate marking of 5-HT axons using a soluble reporter (Migliarini et al, 2013)
These findings clearly demonstrate a requirement for Pet1 in forebrain 5-HT pathway formation and distinct transcription factor requirements in the generation of ascending and descending 5-HT axon projection pathways
Summary
Generated neurons dramatically transform their morphology to establish mature circuit connectivity. Descending 5-HT axons, originating in the medullary serotonergic clusters, raphe pallidus (RPa), raphe obscurus (ROb), and raphe magnus (RMg), enter the spinal cord via the dorsolateral and ventral funiculi These primary projections route medially to invade most lamina of the dorsal and ventral horns as well as the intermediate zone from cervical to sacral levels (Rajaofetra et al, 1989). Lmx1b is a continuously expressed, terminal selector-type factor in 5-HT neurons (Hobert, 2008) raising the possibility that subsequent to its initial role in the induction of 5-HT synthesis and transport it may perform additional stage specific functions in the maturation of serotonergic connectivity. This study demonstrates that a single continuously expressed transcription factor, initially required for induction of 5HT synthesis and reuptake, subsequently acts at successive stages to build the expansive axon pathway architectures enabling CNS-wide serotonergic neuromodulation
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