Lmx1b is required at multiple stages to build expansive serotonergic axon architectures

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.

Serotonergic Axons as Fractional Brownian Motion Paths: Insights Into the Self-Organization of Regional Densities

“…It may be mediated by the brain-derived neurotrophic factor (BDNF) which has long been implicated in the growth of serotonergic fibers (Mamounas et al, 1995 ; Migliarini et al, 2013 ). It remains unclear how serotonin affects fiber densities under physiological conditions because a different genetic model (with a less severe reduction of brain serotonin levels) has failed to reproduce these effects (Donovan et al, 2019 ). Recently, protocadherin-αc2 has been strongly implicated in the distribution of serotonergic fibers, through homophilic interaction between individual axons (Katori et al, 2009 , 2017 ; Chen et al, 2017 ).…”

“…The development of serotonergic fibers is currently conceptualized to proceed in two or three stages: the initial growth in well-defined fiber tracts, followed by extensive arborization and eventual dispersal in “terminal” fields (Lidov and Molliver, 1982 ; Carrera et al, 2008 ; Kiyasova and Gaspar, 2011 ; Jin et al, 2016 ; Maddaloni et al, 2017 ; Donovan et al, 2019 ). This orderly sequence is generally consistent with experimental observations at the level of local fiber populations, visualized with tract-tracing techniques or quantified with density measures.…”

Serotonergic Axons as Fractional Brownian Motion Paths: Insights into the Self-organization of Regional Densities

“…The development of serotonergic fibers is currently conceptualized to proceed in two or three stages: the initial growth in well-defined fiber tracts, followed by extensive arborization and eventual dispersal in "terminal" fields (Lidov and Molliver, 1982;Carrera et al, 2008;Kiyasova and Gaspar, 2011;Jin et al, 2016;Donovan et al, 2019). This orderly sequence is generally consistent with experimental observations at the level of local fiber populations, visualized with tract-tracing techniques or quantified with density measures.…”

“…It may be mediated by the brain-derived neurotrophic factor (BDNF) which has long been implicated in the growth of serotonergic fibers (Mamounas et al, 1995;Migliarini et al, 2013). It remains unclear how serotonin affects fiber densities under physiological conditions because a different genetic model (with a less severe reduction of brain serotonin levels) has failed to reproduce these effects (Donovan et al, 2019). Recently, protocadherin-αc2 has been strongly implicated in the distribution of serotonergic fibers, through homophilic interaction between individual axons (Katori et al, 2009;Chen et al, 2017;Katori et al, 2017).…”

TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

“…This double function differentiates TCF7L2 from the majority of other known terminal selectors, which play minor roles in cell migration or axon guidance ( Hobert, 2016 ), for example habenular selector POU4F2 ( Serrano-Saiz et al, 2018 ). Other examples of terminal selectors that regulate axon guidance are the glutamatergic selector of corticospinal neurons FEZF2 and serotoninergic selector PET1 (FEV) ( Donovan et al, 2019 ; Lodato et al, 2014 ).…”