Developmental timing of hair follicle and dorsal skin innervation in mice

Abstract

The innervation of hair follicles offers an intriguing, yet hardly studied model for the dissection of the stepwise innervation during cutaneous morphogenesis. We have used immunofluorescence and a panel of neuronal markers to characterize the developmental choreography of C57BL/6 mouse backskin innervation. The development of murine skin innervation occurs in successive waves. The first cutaneous nerve fibers appeared before any morphological evidence of hair follicle development at embryonic day 15 (E15). Stage 1 and 2 developing hair follicles were already associated with nerve fibers at E16. These fibers approached a location where later in development the follicular (neural) network A (FNA) is located on fully developed pelage hair follicles. Prior to birth (E18), some nerve fibers had penetrated the epidermis, and an additional set of perifollicular nerve fibers arranged itself around the isthmus and bulge region of stage 5 hair follicles, to develop into the follicular (neural) network B (FNB). By the day of birth (P1), the neuropeptides substance P and calcitonin gene-related peptide became detectable in subcutaneous and dermal nerve fibers first. Newly formed hair follicles on E18 and P1 displayed the same innervation pattern seen in the first wave of hair follicle development. Just prior to epidermal penetration of hair shafts (P5), peptide histidine methionine-IR nerve fibers became detectable and epidermal innervation peaked; such innervation decreased after penetration (P7- P17). Last, tyrosine hydroxylase-IR and neuropeptide Y-IR became readily detectable. This sequence of developing innervation consistently correlates with hair follicle development, indicating a close interdependence of neuronal and epithelial morphogenesis.

Responses of hair follicle–associated structures to loss of planar cell polarity signaling

“…Our time course data confirm previous analyses for these structures (2,10,11,13,21,28), which demonstrated that follicles, sensory afferents, and Merkel cell clusters develop prenatally, whereas APMs and sebaceous glands develop postnatally (Fig. 7).…”

“…If, as suggested by Nurse and Diamond (3), the semicircular arrangement of Merkel cells is important for Follicle-Associated Nerve Endings. Any assessment of the geometry of hair follicle innervation faces the challenge that each follicle is innervated by multiple cutaneous sensory afferents, thus precluding the use of neurofilament immunostaining or other nonselective methods for visualizing the structure of individual afferents (11). Recently, Badea et al (26) described a genetically directed approach for sparse histochemical labeling of individual cutaneous afferents using tamoxifen-controlled neuron-specific Cre recombination to activate the expression of a membraneanchored alkaline phosphatase (AP) reporter.…”

“…In mice, follicles and follicle-associated structures form on different schedules. Guard hair follicles and semicircular Merkel cell clusters are present by embryonic day (E) 16, and follicle-associated lanceolate nerve endings are present by postnatal day (P)0, but sebaceous glands and APMs develop postnatally (2,(10)(11)(12)(13).…”

Balanced levels of nerve growth factor are required for normal pregnancy progression

“…Tissue samples of DBA/2J-or BALB/c-mated CBA/J female mice were perfusion-fixed using a mixture of paraformaldehyde and picric acid (Peters et al 2002). The density of TAC C and CALCA nerve fibres was determined in 14 mm-thick sections.…”

Multipotent skin-derived precursors: adult neural crest-related precursors with therapeutic potential

“…These cells generate diverse peripheral nervous system derivatives, including the peripheral nerves that eventually innervate targets that include the skin. Interestingly, multipotent NC stem cells (NCSCs) are present in the rodent peripheral sciatic nerve at E15 (Morrison et al 1999), the time-point when (i) mouse back skin is first innervated (Peters et al 2002), (ii) SKPs are first detected in mouse back skin (Fernandes et al 2004), and (iii) the follicle dermal papillae first form from a population of cells expressing TrkC and p75NTR (Botchkarev et al 1998(Botchkarev et al , 1999, both of which are expressed on NC precursors (Stemple & Anderson 1992;Luo et al 2003). Within the peripheral nerve, these NCSCs then apparently disappear by birth (Morrison et al 1999), something that has been attributed to their terminal differentiation within the nerve itself.…”