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Endocrinology Vol. 142, No. 6 2533-2539
Copyright © 2001 by The Endocrine Society

ARTICLES

Prolactin Signaling Influences the Timing Mechanism of the Hair Follicle: Analysis of Hair Growth Cycles in Prolactin Receptor Knockout Mice1

A. J. Craven, C. J. Ormandy, F. G. Robertson, R. J. Wilkins, P. A. Kelly, A. J. Nixon and A. J. Pearson

New Zealand Pastoral Agriculture Research Institute (A.J.C., A.J.N., A.J.P.), Hamilton 2020, New Zealand; Cancer Research Program, Garvan Institute of Medical Research (C.J.O., F.G.R.), Darlinghurst, New South Wales 2010, Sydney, Australia; University of Waikato (A.J.C., R.J.W.), Hamilton 2020, New Zealand; and INSERM, U-344, Faculté de Médecine Hopital Necker-Enfants Malades (P.A.K.), Paris 75730, France

Address all correspondence and requests for reprints to: Tony Craven, AgResearch Ruakura, Private Bag 3123, Hamilton, New Zealand. E-mail: cravent{at}agresearch.cri.nz


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Pituitary PRL regulates seasonal hair follicle growth cycles in many mammals. Here we present the first evidence implicating PRL in the nonseasonal, wave-like pelage replacement of laboratory mice. In this study we show that messenger RNA transcripts encoding the one long and two short forms of PRL receptor are present in the skin of adult and neonate mice. The receptor protein was immunolocalized to the hair follicle as well as the epidermis and sebaceous glands. Furthermore, PRL messenger RNA was detected within skin extracts, suggesting a possible autocrine/paracrine role. Analysis of the hair growth phenotype of PRL gene-disrupted mice (PRLR-/-) revealed a change in the timing of hair cycling events. Although no hair follicle development differences were noted in PRLR-/- neonates, observations of the second generation of hair growth revealed PRLR-/- mice molted earlier than wild types (PRLR+/+). The advance was greater in females (29 days) than in males (4 days), resulting in the elimination of the sexual dimorphism associated with murine hair replacement. Heterozygotes were intermediate between PRLR-/- and PRLR+/+ mice in molt onset. Once initiated, the pattern and progression of the molt across the body were similar in all genotypes. Although all fiber types were present and appeared structurally normal, PRLR-/- mice had slightly longer and coarser hair than wild types. These findings demonstrate that PRL has an inhibitory effect on murine hair cycle events. The pituitary PRL regulation of hair follicle cycles observed in seasonally responsive mammals may be a result of pituitary PRL interacting with a local regulatory mechanism.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN LATE GESTATION and early postnatal life, the formation of hair follicles occurs in response to epithelial-mesenchymal interactions (1, 2, 3). After morphogenesis, hair follicles enter a phase of structural regression (catagen) and quiescence (telogen). Follicle reactivation (proanagen) results in the production of a new hair fiber (anagen), allowing the original fiber to eventually be shed. Laboratory rodents grow hair in regular synchronized waves that do not appear to be seasonally driven. In mice, each molt initiates on the belly, spreading symmetrically over the flanks to the back and then to the tail and head (4, 5). Commencing at about 22–28 days of age, this first molt results from production of the second generation (G2) of hair. The control of this pelage growth and replacement process remains poorly understood. The growth phase is initiated by an unidentified intrinsic mechanism (4, 6) modulated by a number of endocrine factors (4, 5, 6, 7, 8).

PRL has been shown to play a role in pelage replacement in a diversity of mammals (9, 10, 11, 12); however, there is little direct evidence implicating PRL in hair growth in nonseasonal species such as humans (13) or laboratory mice. Nevertheless, PRL receptor messenger RNA (mRNA) is present in rat (14) and mouse (15) skin, allowing for a potential physiological role in rodent hair growth. The PRL receptor is a member of the cytokine receptor family. As a result of alternative 3'-exon splicing of a single gene, four mRNA species and their expressed protein isoforms are present in the mouse. The extracellular (exons 4–7) and membrane-proximal (exons 8–9) amino acid sequences are identical, but intracellular domains differ due to the alternative splicing of exons 10, 12, 11, and 13 resulting in one long (PRLRL) and three short (PRLRS1, PRLRS2 and PRLRS3) isoforms (16). Although the ligand may bind to both long and short forms of the receptor, only the PRLRL appears to transmit a signal by recruiting and activating the transcription factor Stat5 (signal transducer and activator of transcription-5) via the mitogen-activated protein kinase pathway (17, 18).

Using gene targeting technology, a mouse strain has been generated lacking functional PRL receptors (PRLR-/-) due to the deletion of exon 5 that codes for amino acids required for ligand binding and receptor activation (19). Previously described phenotypic characteristics of these mice include female infertility due to a modified estrous cycle and failure of implantation, defects in mammary gland development, maternal behavior, and decreased rate of bone formation (19, 20, 21, 22, 23, 24). Although at a gross level PRLR-/- mice appear to grow a normal coat, a detailed study was undertaken to characterize pelage development, growth, and replacement to ascertain whether PRL plays a role in coat replacement in a nonseasonal species.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
RNA isolation and RT-PCR analysis
Skin from the dorsum (adults) or torso (neonates) was collected and immediately frozen in liquid nitrogen before storage at -80 C. Approximately 200 mg frozen skin were ground in a freezer mill (SPEX 7700, Glen Creston, Middlesex, UK), and total RNA was purified using TRIzol reagent (Life Technologies, Inc., Gaithersburg, MD) according to the manufacturer’s instructions. First strand complementary DNA was generated by RT with the Superscript Preamplification System (Life Technologies, Inc.) using the oligo-(deoxythymidine) primers provided. Oligonucleotide primers (Table 1Go), designed using Primer Express software (PE Applied Biosystems, Foster City, CA) from published sequences for murine PRL (25), PRL receptor (16, 26), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (27), were custom synthesized (Life Technologies, Inc.). PCR reactions were set up in 50-µl volumes, consisting of 1 x PCR buffer, 1.5 mm MgCl2, 0.2 mM deoxy-NTPs, 0.2 µm of each PCR primer, 2 µl RT reaction containing first strand complementary DNA, and 2.5 U Taq DNA polymerase (Life Technologies, Inc.). An initial denaturing step at 94 C for 3 min was followed by 25 cycles (GAPDH) or 35 cycles (PRLR and PRL) of annealing at 58 C for 45 sec, 72 C extension for 30 sec, and 94 C denaturation for 30 sec (Corbett 960 Thermocycler, Corbett Research, Sydney, Australia). The PCR products were electrophoresed on 3% agarose gels (Agarose-1000, Life Technologies, Inc.) and scanned using an imaging system (Bio-Rad Laboratories, Inc., Hercules, CA). The identities of PCR products were confirmed by DNA sequencing.


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  		Table 1. PCR primers

 
Immunohistochemistry
Tissue samples fixed in phosphate-buffered 10% formalin and embedded in paraffin wax were serially sectioned (5 µm), and mounted on poly-L-lysine (Sigma, St. Louis, MO)-coated slides. These were dewaxed, washed in citrate buffer (pH 6.0; 10 min), and blocked in 10% normal goat serum/4% BSA (overnight at 4 C) before incubation (1 h at room temperature) with mouse monoclonal anti-PRLR antibody (B6.2) (28), anti-NCA (irrelevant control; B1.1) (28), antiserum raised against ovine PRLR in rabbit (D23; Dr. S. L. Kelly, AgResearch Ruakura, Hamilton, New Zealand), or preimmune serum. Monoclonal antibodies and antisera were diluted in antibody diluent (DAKO Corp., Carpinteria, CA) at 1:500 and 1:1000, respectively. After rinsing in 0.05 M PBS, sections were incubated for 1 h with biotinylated sheep antimouse IgG (Silenus, Melbourne, Australia) or goat antirabbit IgG antibodies (Vector Laboratories, Inc., Burlingame, CA) diluted 1:500 in DAKO Corp. antibody diluent. After three further PBS washes, the sites of antibody binding were visualized with Cy3 dye (Amersham Pharmacia Biotech, Aylesbury, UK), and counterstained with 4',6-diamidine-2-phenylindole dihydrochloride (Molecular Probes, Inc., Eugene, OR) before mounting in fluorescent mounting medium (DAKO Corp., Carpinteria, CA).

Animal experiments
Ten PRLR-/-, 14 PRLR+/-, and 30 129SV wild-type control (PRLR+/+) mice were maintained at the Garvan Institute of Medical Research at 22 C with 12-h light, 12-h dark cycles and 1-h simulated dawn and dusk periods. The genotype of each mouse was determined by PCR of genomic DNA as previously described (19). The mice were fed a diet of formulated mouse pellets ad libitum and had free access to water.

At 22–28 days of age, while the hair follicles were in telogen, the mouse coats were dyed with Durafur black (29). Pelage replacement was then assessed five times per week for 2 weeks, then three times weekly. The age at which renewed follicle growth occurred, as indicated by unstained fibers emerging from the dorsal skin, was recorded. The duration of the G2 growth period at the middorsum was assessed as the period from when fibers emerged through the skin until these fibers reached the length of surrounding unmolted fibers. Body weights were recorded at each observation session.

After the completion of the G2 molt, hair fibers were plucked from the posterior dorsal region of each mouse. The lengths of the primary hairs (awls; 30/mouse) were measured using image analysis. Fibers were also assessed for the mean diameter (n = 4000) and fiber diameter distribution using an Optical Fiber Diameter Analyser (BSC Electronics, Freemantle, Australia). In this way, alterations in the proportions of different fiber populations (monotrichs, awls, auchenes, and zigzags) that differed in diameter could be inferred.

Skin was collected from the dorsal region of six newborn PRLR-/- and six PRLR+/+ mice (day 0) and fixed in phosphate-buffered 10% formalin before processing to paraffin wax. Longitudinal sections were cut (7 µm) and stained using the sacpic method (30). The proportion of 50 follicles/neonate in each developmental stage, according to criteria described by Hardy (2) and Paus (3), and the total follicle density were assessed. All animal experimentation was supervised by the Garvan Institute of Medical Research animal experimentation and ethics committee.

Statistical analysis
Differences in timing of hair cycles, body weights, and fiber characteristics between genotypes were assessed by ANOVA, adjusting for differences in the sex ratio between genotypes. Where indicated, results are presented as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PRLR are present in mouse skin
Transcripts for PRLRL, PRLRS2, and PRLRS3 were shown by RT-PCR analysis to be present in mouse skin containing anagen follicles (Fig. 1Go). Although both long and short isoforms were present in skin, the long form was more highly expressed. PRLRL mRNA was observed in the neonate skin containing developing hair follicles; however, levels were lower than those in the adult. In contrast to mature skin, PRLRS2 or PRLRS3 mRNA was barely detectable in the neonate. The PRLRS1 isoform was not detected in any skin tissue examined. In addition to transcripts coding for PRLR, mRNA for PRL was detected in all skin extracts. PRL mRNA appeared to be more abundant in PRLR-/- than in PRLR+/+ skin.



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  		Figure 1. Expression of PRLR and PRL mRNA in mouse skin. Total RNA samples from skin were analyzed by RT-PCR using oligonucleotides specific for the four isoforms of PRLR and their ligand, PRL. The primers used did not span the disrupted region of the PRLR gene and thus amplified PRLR transcripts in PRLR-/- mice. Equal loadings of RNA were shown by amplification of GAPDH. Products were separated on a 3% agarose gel. The long-form PRLR is expressed in neonatal PRLR+/+ skin and in mature skin.

 
PRLR protein was immunolocalized to hair follicles using two different antibodies (Fig. 2Go). The staining appeared most intense in the outer root sheath of the midshaft region, but was absent in the inner root sheath and dermal papilla. Accessory organs, including sweat and sebaceous glands, and the epidermis were also immunoreactive. Staining was absent from sections incubated with irrelevant antibodies, equivalent concentrations of preimmune serum, coincubation with the antigen, or tissue obtained from PRLR-/- mice.



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  		Figure 2. Immunolocalization of PRLR in murine skin using two different antibodies (B6.2 and D23). PRLR were observed in the sebaceous glands (sg) and epidermis (ep). A, B, D, and I, Within the hair follicle, staining was present in the infundibulum (inf) and outer root sheath (ors), but not in the inner root sheath (irs), hair shaft (hs), or dermal papilla (dp). B, Moderate immunostaining was sometimes apparent in the germinal matrix (gm). No immunostaining was evident in sections incubated with an irrelevant control antibody (B1.1; anti-NCA; E) or preimmune serum (J) or coincubated with the PRLR antigen (K). Staining was considerably reduced in tissue sections with prior exposure to PRL (thus obstructing the epitope; F), and PRLR-/- tissue (G and L). C and H, Sections were counterstained blue with the nuclear stain 4',6-diamidine-2-phenylindole dihydrochloride. Bars, 50 µm.

 
Follicle development
Sections of neonatal (day 0) skin contained a number of initiating follicles varying between developmental stages 1 and 5 and whose distribution was not dependant on genotype (Figs. 3Go). Follicle density (9.4 ± 0.2 follicles/mm2) was neither sex nor genotype dependent.



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  		Figure 3. Neonatal hair follicle morphogenesis appeared normal in PRLR-/- mice. A, Percentage of follicles in each developmental stage present at birth. Three hundred follicles from PRLR-/- and PRLR+/+ neonates (six animals each) were assessed according to the criteria of Hardy and Lyne (2 ). Error bars indicate the SEM. B, Neonatal skin of PRLR-/- mice showed similar structure and stage of development as PRLR+/+ neonatal skin. Bar, 100 µm.

 
Hair cycling is altered in PRLR-/-mice
The newly produced brown fibers of the agouti mice were able to be distinguished against the dark, dyed coat. Hair replacement was advanced in mice deficient in PRLR (Fig. 4Go). In females, fibers erupted on the dorsum by 33.0 ± 0.7 days of age in PRLR-/- mice in contrast to 61.9 ± 2.8 days in PRLR+/+ mice (P < 0.001). PRLR+/- mice were intermediate (50.1 ± 3.2 days of age). In males, a similar effect, but with a much reduced difference between the PRLR-/- and PRLR+/+ genotypes, was observed (31.0 ± 1.0 and 34.9 ± 0.7 days of age, respectively; P < 0.001).



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  		Figure 4. The G2 hair cycle was advanced in PRLR-/- mice. A, Comparison of hair coat color after dyeing at 28 days of age. The PRLR-/- female mouse displayed a completed replacement of G1 hairs at 45 days of age. In contrast, a PRLR+/+ mouse of comparable age showed only partial hair replacement (from the belly to midline; see arrow). B, Bar graph showing the average age at the start of the G2 hair growth phase on the dorsum. Error bars indicate the SEM. C, Photomicrographs comparing dorsal skin of 35-day-old female PRLR+/+ and PRLR-/- mice. While PRLR+/+ hair follicles were in telogen, those of PRLR-/- mice were in anagen (advanced G2 hair cycle). Bar, 200 µm.

 
Pattern of hair renewal in PRLR-/- mice appeared normal
Despite the difference in timing, normal progression of hair replacement across the body was observed in both PRLR+/+ and PRLR-/- mice. New hairs were observed initially in the region under the forelimbs, followed by that under the hindlimbs. Hair renewal then spread across the belly and sides of the mouse. When new hairs were seen on all areas across the back, excluding the rump, pelage replacement was recorded as complete.

Hair fiber structure
All fiber types were present in PRLR-/- animals and were of normal appearance. Male heterozygote and wild-type mice had shorter hair than their female counterparts (Table 2Go). However, PRLR-deficient mice of both sexes had longer hair than normal mice (P < 0.001). After the G2 growth period, PRLR-deficient mice also had slightly coarser hair (P < 0.05) than comparable wild-type animals (Table 2Go), but no difference between sexes was present.


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  		Table 2. Length and diameter of fibers produced during the G2 growth phase (mean ± SEM)

 
Body weights of PRLR-/- mice
At the commencement of the experiment, 28-day-old male mice were heavier than females (P < 0.05), but genotypes of the same sex did not differ significantly (Table 3Go). Among female mice, there was a difference in body weight between genotypes at the completion of their G2 hair cycle, as PRLR-/- mice underwent their G2 hair cycle at a younger age. Female PRLR-/- mice were lighter than both PRLR+/- and PRLR+/+ mice (P < 0.02). Wild-type and heterozygote mice completed their G2 hair cycles at similar weights. There was no significant difference between the body weights of male groups at the completion of their molts.


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  		Table 3. Age and weight at which PRLR genotypes commence the G2 hair growth cycle (mean ± SEM)

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Multiple isoforms of PRLR mRNA are present in murine skin, and receptor protein is present in the hair follicle of wild-type mice (31). PRLRL mRNA appeared to be the most abundant isoform, as it is in the adult ovary (26) and fetal mice (32). Although this pattern of transcript expression was common to both PRLR+/+ and PRLR-/- mice, the disruption of exon 5 in PRLR-/- mice prevented normal translation to a functional protein (19). Hence, although circulating PRL is abnormally high in these mice (20, 24), normal receptor signal transduction is disrupted (19).

In this study we demonstrated that PRL receptor signaling is involved in regulating hair follicle activity in a species with nonseasonal pelage replacement. By dyeing the hair coat of mice during the first postnatal telogen period, the subsequent growth phase was visualized as emerging unstained fibers. The timing was advanced in PRLR null mutant mice compared with wild-type controls. Removal of the pituitary gland has also been shown to advance hair cycles in rats (4, 5, 33). Hypophysectomy at 7 weeks of age advanced the eruption of G2 hairs in the middorsal region and the subsequent G3 hair cycle (4). These researchers suggested that the effect of hypophysectomy was largely due to withdrawal of adrenal and gonadal steroids. In the light of our observations, the loss of PRL caused by hypophysectomy could also have been a factor.

PRLR-deficient mice grew hair that was longer and slightly coarser than their controls. It is not clear whether this is due to an altered rate of keratinocyte proliferation or the duration of growth. However, a difference in length of less than 1.0 mm between genotypes corresponds to less than 24 h of the growth phase, and a quantitative measurement of growth rate would be required to characterize the basis of this observation.

The age at which G2 pelage replacement occurred was also altered in female heterozygotes. Other heterozygote effects have previously been reported. Mammary gland development and lactation were impaired (19, 22), but to a lesser extent than in PRLR-/- mice. Maternal behavioral traits (21) and bone formation (20) were also intermediate in heterozygotes. These findings suggest a graduated response whereby two functional alleles of the PRLR gene are required to achieve normal levels of cellular signal processing. Impairment of one allele results in an attenuation of gene function. Hence, an increase in capacity for PRL signaling appears to correlate with the delay of molt onset. In support of this, pelage replacement is delayed in wild-type females whose serum PRL concentrations are generally greater than males. Although this difference in circulating PRL is strain dependent (34), it is evident in the 129SV mice used in this study (our unpublished data). On the other hand, as PRLR+/- mice have similar PRL profiles as wild-type mice (24) but advanced hair cycles, this effect is likely to arise downstream from the circulating PRL concentration.

Pelage replacement was advanced by 4 days in male knockouts compared with a 4-week advancement in female knockouts, virtually eliminating the normal sexual dimorphism observed in G2 hair growth initiation. The advancement of the female hair cycles from 62 to 33 days of age places pelage replacement within the normal age range for male regrowth as reported here and previously (4, 35, 36). Interestingly, the sexual dimorphism in both fiber length and diameter observed among wild types was also eliminated.

PRLR have previously been localized to adult rat skin (37), human epidermal cells (38), and wool follicles in sheep (39, 40). The distribution of PRLR observed in this study was similar to that reported in sheep, but with the notable absence of receptors in the dermal papillae of mice. In day 14–18 fetal mice, when hair follicle initiation is commencing, the liver, kidneys, thymus, spleen, adrenals, and pituitary gland commence expression of PRLR (15, 32, 41). Using RT-PCR analysis we have shown that mRNA of PRLRL is present in mouse skin at birth. In contrast, Brown-Borg et al. (41) reported that skin tissue from 2-day postnatal mice exhibited no PRLR expression. However, the apparently normal skin organogenesis in PRLR-deficient neonates suggests that PRL plays no essential role in the embryonic development of murine hair follicles.

The local production of PRL observed in this study may provide an autocrine/paracrine mechanism to regulate hair follicle activity (31, 42) as also shown in sheep (43). Photoperiod-influenced pituitary PRL secretion, characteristic of mammals with seasonal hair growth, may interact with a local regulatory mechanism common to all mammals. It is noteworthy that skin from PRLR-/- mice have abnormally high levels of both PRL mRNA and protein (24), suggesting that receptor signaling down-regulates synthesis of the ligand.

Although a direct effect of PRL is the most likely explanation for the timing differences in G2 hair replacement, we cannot exclude an indirect effect via other hormones perturbed in PRLR knockout mice. Circulating concentrations of estradiol are lower in female knockout mice at estrous (37 pg/ml compared with 53 pg/ml in wild-type mice) (20). Estradiol has been shown to have direct inhibitory effects on fiber growth cycles (4, 5, 6), and estradiol receptors have been located in the dermal papillae of telogen follicles (6). On the other hand, the observed hair growth responses to disrupted PRL signaling are unlikely to be solely due to a small decrease in estrogen. Progesterone levels are also lower in PRLR-deficient females at estrus compared with those in wild-type mice (6.8 ng/ml compared with 17.9 ng/ml) (20). Progesterone is reported to up-regulate PRLR, whereas PRL up-regulates the progesterone receptor in mouse mammary glands (44) and human breast cancer cells (45, 46). Furthermore, the progesterone receptor may interact with the signal transducer Stat5a (47). However, no direct effects of progesterone on rodent hair growth have been reported (5). Higher levels of PTH are found in both male and female PRLR-deficient mice (53 pg/ml compared with 23 pg/ml) (20). Administration of PTH also accelerates anagen development in telogen follicles in mice (7). Furthermore, this hormone prolongs anagen and thus could explain the slightly longer hair length in PRLR-deficient mice. However, as both male and female PRLR-deficient mice have similarly increased PTH levels, the greater advancement of anagen in females is not explained by PTH acting alone.

Both PRLR and PRL transcripts in mouse skin have been demonstrated, and PRLR has been localized to the hair follicle. These receptors do not appear to have an essential function in follicle morphogenesis during embryonic development. However, disruption of this hormone axis shortens the quiescent phase of the hair follicle. PRL, directly or indirectly, appears to be inhibitory to the growth processes of the murine hair follicle by delaying the proliferative processes involved in the reactivation of follicles from telogen to anagen. In addition, PRL may influence, albeit to a lesser degree, the proliferation or elongation of keratinocytes during fiber formation. Further understanding of the regulation of PRL and its receptors in relation to hair cycle events and the downstream response elements regulated by the receptor activation may elucidate the mechanism controlling hair growth cyclicity.


   Acknowledgments
 
We gratefully acknowledge the assistance provided by the staff of the Garvan Institute of Medical Research animal house. Dr. Barbara Vonderhaar generously supplied the B6.2 and B1.1 antibodies. We also thank Dr. Sharon Kelly for assistance with the immunohistochemistry, Dr. Helen Davey for her support and encouragement of this work, and Prof. Ralf Paus for his comments on the manuscript.


   Footnotes
 
1 This work was supported by the New Zealand Foundation for Research, Science, and Technology and the National Health and Medical Research Council of Australia. Back

Received October 24, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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