Slit2, a Multifaceted Guidance Cue, Essential for Establishing Proper Sympathetic Innervation Architecture
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Authors
Soto Ortega, Analilia
Issue Date
2025
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Sympathetic innervation is essential for adipose tissue function, yet the developmental cues thatshape these neural circuits remain undefined. Here, we identify SLIT2 as a critical regulator of
sympathetic patterning in embryonic adipose tissue and demonstrate that its proteolytic
processing is required to balance axon restriction and branching. Loss of Slit2 (Slit2−/−) caused
excessive sympathetic arborization, whereas cleavage-resistant Slit2 (Slit2ΔTLS/−) produced
diminished branching and expanded gaps in innervation. Robo1/2 knockouts phenocopied Slit2
loss, establishing that Slit2 signals through ROBO receptors, while Tll1 deficiency mirrored the
Slit2ΔTLS phenotype, confirming that Slit2 proteolysis is required in vivo. Using PDGFRα-
directed deletion, we identify stromal precursors and adipocytes as a key tissue source of Slit2.
Finally, SCG neuron cultures reveal fragment-specific effects of SLIT2-FL, SLIT2-N, and
SLIT2-C on neurite morphology. Together, these findings define Slit2 cleavage as a mechanism
that sculpts sympathetic innervation of adipose tissue and suggest that altered Slit2 signaling may
influence long-term adipose metabolic function.