Hair follicles modulate skin barrier function.

Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with the interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell-autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing IL-17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.

Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.

The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.

Hair follicles modulate skin barrier function.

Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing Il17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.

Preparing the hair follicle canal for hair shaft emergence.

The emergence of hair is a defining event during mammalian skin development, but the cellular mechanisms leading to the opening of the hair follicle canal remain poorly characterized. Our previous studies have shown that early hair buds possess a central column of differentiated keratinocytes expressing Keratin 79 (K79), which marks the future hair follicle opening. Here, we report that during late embryogenesis and early postnatal development, K79+ cells at the distal tips of these columns downregulate E-cadherin, change shape, recede and undergo cell death. These changes likely occur independently of sebaceous glands and the growing hair shaft, and serve to create an orifice for hair to subsequently emerge. Defects in this process may underlie phenomena such as ingrown hair or may potentially contribute to upper hair follicle pathologies including acne, hidradenitis suppurativa and infundibular cysts.