Sexually Dimorphic BDNF Signaling Directs Sensory Innervation of the Mammary Gland

Male and female mice differ in the neuronal patterns that serve the mammary glands. Yin Liu et al. (p. 1357) now describe how gonadal hormones drive development of distinct male and female sensory innervations. Although both male and female mammary glands develop their sensory innervation similarly in early embryogenesis, once the androgens take effect, the developmental trajectories diverge. By birth, the rich network of sensory neurons present in the female is absent in the male. Androgens cause a switch from expression of the full-length neurotrophin receptor TrkB to its truncated form, TrkB.T1, both of which are expressed on the neurons. In males, truncated TrkB.T1 sequesters brain-derived neurotrophic factor (BDNF) from further activity, whereas in females, full-length TrkB binds BDNF and supports neuronal development. Androgen-driven changes in receptor expression disrupt a neuronal signaling pathway and de-innervation. How neural circuits associated with sexually dimorphic organs are differentially assembled during development is unclear. Here, we report a sexually dimorphic pattern of mouse mammary gland sensory innervation and the mechanism of its formation. Brain-derived neurotrophic factor (BDNF), emanating from mammary mesenchyme and signaling through its receptor TrkB on sensory axons, is required for establishing mammary gland sensory innervation of both sexes at early developmental stages. Subsequently, in males, androgens promote mammary mesenchymal expression of a truncated form of TrkB, which prevents BDNF-TrkB signaling in sensory axons and leads to a rapid loss of mammary gland innervation independent of neuronal apoptosis. Thus, sex hormone regulation of a neurotrophic factor signal directs sexually dimorphic axonal growth and maintenance, resulting in generation of a sex-specific neural circuit.