The hair follicle (HF) has a wide range of functions including thermoregulation, physical and immunological protection against external insults, sensory perception, social interactions, and camouflage. One of the most characteristic features of HFs is that they self-renew during hair cycle (HC) throughout the entire life of an individual to continuously produce new hair. HC disturbances are common in humans and comparable to some alopecic disorders in dogs. A normal HC is maintained by follicular stem cells (SCs), which are predominately found in an area known as the bulge. Due to similar morphological characteristics of the human and canine bulge area, the particularity of compound HFs in humans and dogs as well as similarities in follicular biomarker expression, the dog might be a promising model to study human HC and SC disorders. In this review, we give an overview of normal follicular anatomy, the HC, and follicular SCs and discuss the possible pathogenetic mechanisms of noninflammatory alopecia.

Diseases affecting the hair follicle are common in domestic animals, but despite the importance of an intact skin barrier and a fully functional hair coat, knowledge about the detailed morphological features and the diversity of these complex mini-organs are often limited, although mandatory to evaluate skin biopsies with a history of alopecia. The factors that regulate the innate hair follicle formation and the postnatal hair cycle are still not completely understood in rodents, only rudimentarily known in humans, and are poorly understood in our companion animals. This review aims to summarize the current knowledge about hair follicle and hair shaft anatomy, the arrangement of hair follicles, hair follicle morphogenesis in the embryo, and the lifelong regeneration during the postnatal hair cycle in domestic animals. The role of follicular stem cells and the need for a multitude of interacting signaling events during hair follicle morphogenesis and regeneration is unquestioned. Because of the lack of state of the art methods that can be applied in rodents but are not feasible in companion animals, most of the information in this review is based on rodent studies. However, the few data from domestic animals that are available will be discussed, and it can be assumed that at least the principal molecular mechanisms are similar in rodents and other species.

Alopecia X is a hair cycle arrest disorder in Pomeranians. Histologically, kenogen and telogen hair follicles predominate, whereas anagen follicles are sparse. The induction of anagen relies on the activation of hair follicle stem cells and their subsequent proliferation and differentiation. Stem cell function depends on finely tuned interactions of signaling molecules and transcription factors, which are not well defined in dogs. We performed transcriptome profiling on skin biopsies to analyze altered molecular pathways in alopecia X. Biopsies from five affected and four non-affected Pomeranians were investigated. Differential gene expression revealed a downregulation of key regulator genes of the Wnt (CTNNB1, LEF1, TCF3, WNT10B) and Shh (SHH, GLI1, SMO, PTCH2) pathways. In mice it has been shown that Wnt and Shh signaling results in stem cell activation and differentiation Thus our findings are in line with the lack of anagen hair follicles in dogs with Alopecia X. We also observed a significant downregulation of the stem cell markers SOX9, LHX2, LGR5, TCF7L1 and GLI1 whereas NFATc1, a quiescence marker, was upregulated in alopecia X. Moreover, genes coding for enzymes directly involved in the sex hormone metabolism (CYP1A1, CYP1B1, HSD17B14) were differentially regulated in alopecia X. These findings are in agreement with the so far proposed but not yet proven deregulation of the sex hormone metabolism in this disease.

Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo. Lethal acrodermatitis (LAD) is an autosomal recessive hereditary disease in dogs. It is characterized by poor growth, immune deficiency and characteristic skin lesions of the paws and of the face. We mapped the LAD locus to a ~1.11 Mb segment on canine chromosome 14. Whole genome sequence data of an LAD affected dog and 191 controls revealed a candidate causative variant in the MKLN1 gene, encoding muskelin 1. The identified variant, a single nucleotide substitution, MKLN1:c.400+3A>C, altered the 5’-splice site at the beginning of intron 4. We experimentally confirmed that this variant leads to complete skipping of exon 4 in the MKLN1 mRNA in skin. Various cellular functions have been postulated for muskelin 1 including roles in intracellular transport processes, cell morphology, cell spreading, and cell adhesion. Our data from dogs reveal a novel in vivo role for muskelin 1 that is related to the immune system and skin. MKLN1 thus represents a novel candidate gene for human patients with unsolved acrodermatitis and/or immune deficiency phenotypes. LAD affected dogs may serve as models to gain more insights into the function of muskelin 1.