Talk:Integumentary System - Hair Development

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Cite this page: Hill, M.A. (2021, December 4) Embryology Integumentary System - Hair Development. Retrieved from


Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent

Dev Cell. 2019 Jan 7;48(1):32-48.e5. doi: 10.1016/j.devcel.2018.11.034. Epub 2018 Dec 27.

Mok KW1, Saxena N2, Heitman N2, Grisanti L1, Srivastava D1, Muraro MJ3, Jacob T4, Sennett R1, Wang Z5, Su Y6, Yang LM6, Ma'ayan A5, Ornitz DM6, Kasper M4, Rendl M7. Author information Abstract Cell fate transitions are essential for specification of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we identify, with 3D and 4D microscopy, unclustered precursors of dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes. With population-based and single-cell transcriptomics, we define a molecular time-lapse from pre-DC fate specification through DC niche formation and establish the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then coincide with DC formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for pre-DC specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.

Copyright © 2018 Elsevier Inc. All rights reserved.

KEYWORDS: cell fate specification; dermal condensate precursors; dermal papilla; hair follicle formation; hair follicle morphogenesis; placode progenitors; single cell; stem cell niche PMID: 30595537 DOI: 10.1016/j.devcel.2018.11.034


Dynamic Nestin expression during hair follicle maturation and the normal hair cycle

Mol Med Rep. 2018 Nov 26. doi: 10.3892/mmr.2018.9691. [Epub ahead of print]

Chen R1, Miao Y1, Hu Z1.


Nestin, a type-VI intermediate filament protein, serves as a marker for neural stem cells, and is also known to be expressed in follicle stem cells. Hair follicles go through repeated cycles of anagen (growth), catagen (regression) and telogen (quiescence) throughout the life of mammals following morphogenesis. In the present study it was demonstrated that in mice, the maturation of hair follicles includes the period between morphogenesis and the first anagen (4 weeks of age). Skin samples from Nestin‑green fluorescent protein (GFP)+ mice at different hair follicle stages were collected, and immunostaining for Nestin and Ki67 was performed. It was identified that during morphogenesis, Nestin‑GFP expression was rarely detected and it gradually increased during maturation (0‑4 weeks) in hair follicle dermal cells. In mature hair follicle dermal cells, Nestin and the proliferation marker Ki67 were highly expressed in anagen, while during telogen, they were markedly decreased. Additionally, lineage tracing data demonstrated that peri‑follicular Nestin+ cells during morphogenesis differentiated into cluster of differentiation 31+ cells.

PMID: 30483790 DOI: 10.3892/mmr.2018.9691


ILK modulates epithelial polarity and matrix formation in hair follicles

Mol Biol Cell. 2014 Mar;25(5):620-32. doi: 10.1091/mbc.E13-08-0499. Epub 2013 Dec 26.

Rudkouskaya A1, Welch I, Dagnino L. Author information


Hair follicle morphogenesis requires coordination of multiple signals and communication between its epithelial and mesenchymal constituents. Cell adhesion protein platforms, which include integrins and integrin-linked kinase (ILK), are critical for hair follicle formation. However, their precise contribution to this process is poorly understood. We show that in the absence of ILK, the hair follicle matrix lineage fails to develop, likely due to abnormalities in development of apical-basal cell polarity, as well as in laminin-511 and basement membrane assembly at the tip of the hair bud. These defects also result in impaired specification of hair matrix and absence of precortex and inner sheath root cell lineages. The molecular pathways affected in ILK-deficient follicles are similar to those in the absence of epidermal integrin β1 and include Wnt, but not sonic hedgehog, signaling. ILK-deficient hair buds also show abnormalities in the dermal papilla. Addition of exogenous laminin-511 restores morphological and molecular markers associated with hair matrix formation, indicating that ILK regulates hair bud cell polarity and functions upstream from laminin-511 assembly to regulate the developmental progression of hair follicles beyond the germ stage.

PMID 24371086


β1 integrin signaling maintains human epithelial progenitor cell survival in situ and controls proliferation, apoptosis and migration of their progeny

PLoS One. 2013 Dec 27;8(12):e84356. doi: 10.1371/journal.pone.0084356. eCollection 2013.

Ernst N1, Yay A2, Bíró T3, Tiede S4, Humphries M5, Paus R6, Kloepper JE1. Author information


β1 integrin regulates multiple epithelial cell functions by connecting cells with the extracellular matrix (ECM). While β1 integrin-mediated signaling in murine epithelial stem cells is well-studied, its role in human adult epithelial progenitor cells (ePCs) in situ remains to be defined. Using microdissected, organ-cultured human scalp hair follicles (HFs) as a clinically relevant model for studying human ePCs within their natural topobiological habitat, β1 integrin-mediated signaling in ePC biology was explored by β1 integrin siRNA silencing, specific β1 integrin-binding antibodies and pharmacological inhibition of integrin-linked kinase (ILK), a key component of the integrin-induced signaling cascade. β1 integrin knock down reduced keratin 15 (K15) expression as well as the proliferation of outer root sheath keratinocytes (ORSKs). Embedding of HF epithelium into an ECM rich in β1 integrin ligands that mimic the HF mesenchyme significantly enhanced proliferation and migration of ORSKs, while K15 and CD200 gene and protein expression were inhibited. Employing ECM-embedded β1 integrin-activating or -inhibiting antibodies allowed to identify functionally distinct human ePC subpopulations in different compartments of the HF epithelium. The β1 integrin-inhibitory antibody reduced β1 integrin expression in situ and selectively enhanced proliferation of bulge ePCs, while the β1 integrin-stimulating antibody decreased hair matrix keratinocyte apoptosis and enhanced transferrin receptor (CD71) immunoreactivity, a marker of transit amplifying cells, but did not affect bulge ePC proliferation. That the putative ILK inhibitor QLT0267 significantly reduced ORSK migration and proliferation and induced massive ORSK apoptosis suggests a key role for ILK in mediating the ß1 integrin effects. Taken together, these findings demonstrate that ePCs in human HFs require β1 integrin-mediated signaling for survival, adhesion, and migration, and that different human HF ePC subpopulations differ in their response to β1 integrin signaling. These insights may be exploited for cell-based regenerative medicine strategies that employ human HF-derived ePCs. PMID 24386370



Notch signaling regulates late-stage epidermal differentiation and maintains postnatal hair cycle homeostasis

PLoS One. 2011 Jan 18;6(1):e15842.

Lin HY, Kao CH, Lin KM, Kaartinen V, Yang LT. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan, Republic of China.


BACKGROUND: Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis.

METHODOLOGY AND PRINCIPAL FINDINGS: We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes.

SIGNIFICANCE: our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells.

PMID: 21267458


Cyclic expression of lhx2 regulates hair formation

Törnqvist G, Sandberg A, Hägglund AC, Carlsson L. PLoS Genet. 2010 Apr 8;6(4):e1000904. PMID: 20386748

Hair is important for thermoregulation, physical protection, sensory activity, seasonal camouflage, and social interactions. Hair is generated in hair follicles (HFs) and, following morphogenesis, HFs undergo cyclic phases of active growth (anagen), regression (catagen), and inactivity (telogen) throughout life. The transcriptional regulation of this process is not well understood. We show that the transcription factor Lhx2 is expressed in cells of the outer root sheath and a subpopulation of matrix cells during both morphogenesis and anagen. As the HFs enter telogen, expression becomes undetectable and reappears prior to initiation of anagen in the secondary hair germ. In contrast to previously published results, we find that Lhx2 is primarily expressed by precursor cells outside of the bulge region where the HF stem cells are located. This developmental, stage- and cell-specific expression suggests that Lhx2 regulates the generation and regeneration of hair. In support of this hypothesis, we show that Lhx2 is required for anagen progression and HF morphogenesis. Moreover, transgenic expression of Lhx2 in postnatal HFs is sufficient to induce anagen. Thus, our results reveal an alternative interpretation of Lhx2 function in HFs compared to previously published results, since Lhx2 is periodically expressed, primarily in precursor cells distinct from those in the bulge region, and is an essential positive regulator of hair formation.

Characterization of the correlation between ages at entry into breast and pubic hair development

Ann Epidemiol. 2010 May;20(5):405-8.

Christensen KY, Maisonet M, Rubin C, Flanders WD, Drews-Botsch C, Dominguez C, McGeehin MA, Marcus M.

Epidemiology Department, Emory University, Atlanta, GA 30322, USA. Abstract PURPOSE: The timing of breast and pubic hair development in girls are related, but the degree of correlation has not been well characterized. Periodic observations also are complicated by interval censoring.

METHODS: Data used were from the Avon Longitudinal Study of Parents and Children. Mean age at entry into breast and pubic hair development was determined by the use of parametric survival analysis. The bivariate normal cumulative distribution function was evaluated over the region containing the paired event times; the likelihood was maximized with respect to the correlation coefficient rho.

RESULTS: Among 3938 participants, estimated mean ages at entry into Tanner stage 2 for breast and pubic hair development were 10.19 and 10.95, respectively. The likelihood was maximized at rho = 0.503 to 0.506. This value remained relatively constant among subgroups, although some heterogeneity was observed by maternal and child body mass index and birth order.

CONCLUSIONS: The timing of breast and of pubic hair development is moderately correlated and remain so when it is stratified by characteristics associated with puberty.

PMID: 20382343

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(see also Genital System Development)

Original Page References


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Schmidt-Ullrich R, Paus R. Molecular principles of hair follicle induction and morphogenesis. Bioessays. 2005 Mar;27(3):247-61.

Ahmad W, Panteleyev AA, Christiano AM. The molecular basis of congenital atrichia in humans and mice: mutations in the hairless gene. J Investig Dermatol Symp Proc. 1999 Dec;4(3):240-3.

Ebling FJ. Hair follicles and associated glands as androgen targets. Clin Endocrinol Metab. 1986 May;15(2):319-39.


Wang Y, Badea T, Nathans J. Order from disorder: Self-organization in mammalian hair patterning. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19800-5. Epub 2006 Dec 15. PNAS Link

Ouji Y, Yoshikawa M, Shiroi A, Ishizaka S. Promotion of hair follicle development and trichogenesis by Wnt-10b in cultured embryonic skin and in reconstituted skin. Biochem Biophys Res Commun. 2006 Jun 30;345(2):581-7.

Cui CY, Hashimoto T, Grivennikov SI, Piao Y, Nedospasov SA, Schlessinger D. Ectodysplasin regulates the lymphotoxin-{beta} pathway for hair differentiation. Proc Natl Acad Sci U S A. 2006 May 31

Search NCBI Bookshelf: Bookshelf - hair development

Developmental Biology - Development of the hair follicles in fetal human skin | Eurekah Bioscience Collection - Role of GLI proteins in embryonic hair follicle development | Molecular Biology of the Cell - FGF5 is a negative regulator of hair formatio

Search PubMed: Search May 2006 "hair development" 6,574 reference articles of which 813 were reviews.

Search term = hair development | hair follicle development | lanugo hair