Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.

Department of Cell Biology Faculty of Science Charles University Brno Czech Republic

Department of Developmental Biology Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic

Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic

Laboratory of Transcriptional Regulation Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic

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doi: 10.1101/2024.08.13.607774 PubMed

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doi: 10.7554/eLife.100854.1 PubMed

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doi: 10.7554/eLife.100854.2 PubMed

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Adameyko I, Fried K. The nervous system orchestrates and integrates craniofacial development: A review. Frontiers in Physiology. 2016;7:49. doi: 10.3389/fphys.2016.00049. PubMed DOI PMC

Andrés FL, Van der Loos H. Whisker patterns form in cultured non-innervated muzzle skin from mouse embryos. Neuroscience Letters. 1982;30:37–41. doi: 10.1016/0304-3940(82)90008-8. PubMed DOI

Andrés FL, Van Der Loos H. Cultured embryonic non-innervated mouse muzzle is capable of generating a whisker pattern. International Journal of Developmental Neuroscience. 1983;1:319–338. doi: 10.1016/0736-5748(83)90034-5. PubMed DOI

Biggs LC, Mäkelä OJ, Myllymäki SM, Das Roy R, Närhi K, Pispa J, Mustonen T, Mikkola ML. Hair follicle dermal condensation forms via Fgf20 primed cell cycle exit, cell motility, and aggregation. eLife. 2018;7:e36468. doi: 10.7554/eLife.36468. PubMed DOI PMC

Botchkarev VA, Danielian PS, Dassule HR, Karavanova I, Li J, Lewis PM, McMahon JA, McMahon AP, Paus R, St-Jacques B. Sonic hedgehog signaling is essential for hair development. Current Biology. 1998;8:1058–1068. doi: 10.1016/s0960-9822(98)70443-9. PubMed DOI

Chen D, Jarrell A, Guo C, Lang R, Atit R. Dermal β-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development. 2012;139:1522–1533. doi: 10.1242/dev.076463. PubMed DOI PMC

Cheng HJ, Bagri A, Yaron A, Stein E, Pleasure SJ, Tessier-Lavigne M. Plexin-A3 mediates semaphorin signaling and regulates the development of hippocampal axonal projections. Neuron. 2001;32:249–263. doi: 10.1016/s0896-6273(01)00478-0. PubMed DOI

DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development. 1999;126:4557–4568. doi: 10.1242/dev.126.20.4557. PubMed DOI

Davies AM, Lumsden AG. Fasciculation in the early mouse trigeminal nerve is not ordered in relation to the emerging pattern of whisker follicles. The Journal of Comparative Neurology. 1986;253:13–24. doi: 10.1002/cne.902530103. PubMed DOI

Dent EW, Barnes AM, Tang F, Kalil K. Netrin-1 and semaphorin 3A promote or inhibit cortical axon branching, respectively, by reorganization of the cytoskeleton. The Journal of Neuroscience. 2004;24:3002–3012. doi: 10.1523/JNEUROSCI.4963-03.2004. PubMed DOI PMC

Duan Y, Liang Y, Yang F, Ma Y. Neural regulations in tooth development and tooth-periodontium complex homeostasis: A literature review. International Journal of Molecular Sciences. 2022;23:14150. doi: 10.3390/ijms232214150. PubMed DOI PMC

Erdélyi G, Fried K, Hildebrand C. Nerve growth to tooth buds after homotopic or heterotopic autotransplantation. Developmental Brain Research. 1987;33:39–47. doi: 10.1016/0165-3806(87)90174-X. PubMed DOI

Fabik J, Kovacova K, Kozmik Z, Machon O. Neural crest cells require Meis2 for patterning the mandibular arch via the Sonic hedgehog pathway. Biology Open. 2020;9:052043. doi: 10.1242/bio.052043. PubMed DOI PMC

Ge W, Tan SJ, Wang SH, Li L, Sun XF, Shen W, Wang X. Single-cell transcriptome profiling reveals dermal and epithelial cell fate decisions during embryonic hair follicle development. Theranostics. 2020;10:7581–7598. doi: 10.7150/thno.44306. PubMed DOI PMC

Glover JD, Wells KL, Matthäus F, Painter KJ, Ho W, Riddell J, Johansson JA, Ford MJ, Jahoda CAB, Klika V, Mort RL, Headon DJ. Hierarchical patterning modes orchestrate hair follicle morphogenesis. PLOS Biology. 2017;15:e2002117. doi: 10.1371/journal.pbio.2002117. PubMed DOI PMC

Gupta K, Levinsohn J, Linderman G, Chen D, Sun TY, Dong D, Taketo MM, Bosenberg M, Kluger Y, Choate K, Myung P. Single-cell analysis reveals a hair follicle dermal niche molecular differentiation trajectory that begins prior to morphogenesis. Developmental Cell. 2019;48:17–31. doi: 10.1016/j.devcel.2018.11.032. PubMed DOI PMC

Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, Hoffman P, Stoeckius M, Papalexi E, Mimitou EP, Jain J, Srivastava A, Stuart T, Fleming LM, Yeung B, Rogers AJ, McElrath JM, Blish CA, Gottardo R, Smibert P, Satija R. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573–3587. doi: 10.1016/j.cell.2021.04.048. PubMed DOI PMC

Hudacova E, Abaffy P, Kaplan MM, Krausova M, Kubista M, Machon O. Single-cell transcriptomic resolution of osteogenesis during craniofacial morphogenesis. Bone. 2025;190:117297. doi: 10.1016/j.bone.2024.117297. PubMed DOI

Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;105:533–545. doi: 10.1016/s0092-8674(01)00336-1. PubMed DOI

Huh SH, Närhi K, Lindfors PH, Häärä O, Yang L, Ornitz DM, Mikkola ML. Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles. Genes & Development. 2013;27:450–458. doi: 10.1101/gad.198945.112. PubMed DOI PMC

Kaplan MM. Whisker_scRNA. swh:1:rev:acb01843bee3a40f97987c8bce2d4deeac20a77bSoftware Heritage. 2025 https://archive.softwareheritage.org/swh:1:dir:a262681da0087d4b73deb245990dde371adeea4a;origin=https://github.com/kaplanmm/whisker_scRNA;visit=swh:1:snp:13acd9d21a0c017a2ab445a68703e8ed3f480451;anchor=swh:1:rev:acb01843bee3a40f97987c8bce2d4deeac20a77b

Kaukua N, Shahidi MK, Konstantinidou C, Dyachuk V, Kaucka M, Furlan A, An Z, Wang L, Hultman I, Ahrlund-Richter L, Blom H, Brismar H, Lopes NA, Pachnis V, Suter U, Clevers H, Thesleff I, Sharpe P, Ernfors P, Fried K, Adameyko I. Glial origin of mesenchymal stem cells in a tooth model system. Nature. 2014;513:551–554. doi: 10.1038/nature13536. PubMed DOI

Kratochwil K, Dull M, Farinas I, Galceran J, Grosschedl R. Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes & Development. 1996;10:1382–1394. doi: 10.1101/gad.10.11.1382. PubMed DOI

Leonard CE, Quiros J, Lefcort F, Taneyhill LA. Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia. eLife. 2022;11:e71455. doi: 10.7554/eLife.71455. PubMed DOI PMC

Lewis AE, Vasudevan HN, O’Neill AK, Soriano P, Bush JO. The widely used Wnt1-Cre transgene causes developmental phenotypes by ectopic activation of Wnt signaling. Developmental Biology. 2013;379:229–234. doi: 10.1016/j.ydbio.2013.04.026. PubMed DOI PMC

Lillesaar C, Hildebrand C. Denervation does not affect the growth of rat vibrissae. Neuroscience Letters. 1999;261:69–72. doi: 10.1016/s0304-3940(98)01015-5. PubMed DOI

Løes S, Kettunen P, Kvinnsland I, Luukko K. Mouse rudimentary diastema tooth primordia are devoid of peripheral nerve fibers. Anatomy and Embryology. 2002;205:187–191. doi: 10.1007/s00429-002-0247-8. PubMed DOI

Lumsden AG, Buchanan JA. An experimental study of timing and topography of early tooth development in the mouse embryo with an analysis of the role of innervation. Archives of Oral Biology. 1986;31:301–311. doi: 10.1016/0003-9969(86)90044-0. PubMed DOI

Ma Q, Chen Z, del Barco Barrantes I, de la Pompa JL, Anderson DJ. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron. 1998;20:469–482. doi: 10.1016/s0896-6273(00)80988-5. PubMed DOI

Machon O, Backman M, Machonova O, Kozmik Z, Vacik T, Andersen L, Krauss S. A dynamic gradient of Wnt signaling controls initiation of neurogenesis in the mammalian cortex and cellular specification in the hippocampus. Developmental Biology. 2007;311:223–237. doi: 10.1016/j.ydbio.2007.08.038. PubMed DOI

Machon O, Masek J, Machonova O, Krauss S, Kozmik Z. Meis2 is essential for cranial and cardiac neural crest development. BMC Developmental Biology. 2015;15:40. doi: 10.1186/s12861-015-0093-6. PubMed DOI PMC

Maeda Y, Miwa Y, Sato I. Distribution of the neuropeptide calcitonin gene-related peptide-α of tooth germ during formation of the mouse mandible. Annals of Anatomy = Anatomischer Anzeiger. 2019;221:38–47. doi: 10.1016/j.aanat.2018.09.001. PubMed DOI

Mäkelä OJM, Mikkola ML. Mesenchyme governs hair follicle induction. Development. 2023;150:dev202140. doi: 10.1242/dev.202140. PubMed DOI

Maklad A, Conway M, Hodges C, Hansen LA. Development of innervation to maxillary whiskers in mice. The Anatomical Record. 2010;293:1553–1567. doi: 10.1002/ar.21194. PubMed DOI

Manti PG, Darbellay F, Leleu M, Coughlan AY, Moret B, Cuennet J, Droux F, Stoudmann M, Mancini GF, Hautier A, Sordet-Dessimoz J, Vincent SD, Testa G, Cossu G, Barrandon Y. The transcriptional regulator Prdm1 is essential for the early development of the sensory whisker follicle and is linked to the beta-catenin first dermal signal. Biomedicines. 2022;10:2647. doi: 10.3390/biomedicines10102647. PubMed DOI PMC

Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, Hassan AB, Volpin D, Bressan GM, Piccolo S. Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. PNAS. 2003;100:3299–3304. doi: 10.1073/pnas.0434590100. PubMed DOI PMC

Matos I, Asare A, Levorse J, Ouspenskaia T, de la Cruz-Racelis J, Schuhmacher LN, Fuchs E. Progenitors oppositely polarize WNT activators and inhibitors to orchestrate tissue development. eLife. 2020;9:e54304. doi: 10.7554/eLife.54304. PubMed DOI PMC

Moe K, Sijaona A, Shrestha A, Kettunen P, Taniguchi M, Luukko K. Semaphorin 3A controls timing and patterning of the dental pulp innervation. Differentiation; Research in Biological Diversity. 2012;84:371–379. doi: 10.1016/j.diff.2012.09.003. PubMed DOI

Moiseiwitsch JRD, Lauder JM. Stimulation of murine tooth development in organotypic culture by the neurotransmitter serotonin. Archives of Oral Biology. 1996;41:161–165. doi: 10.1016/0003-9969(95)00117-4. PubMed DOI

Mok KW, Saxena N, Heitman N, Grisanti L, Srivastava D, Muraro MJ, Jacob T, Sennett R, Wang Z, Su Y, Yang LM, Ma’ayan A, Ornitz DM, Kasper M, Rendl M. Dermal condensate niche fate specification occurs prior to formation and is placode progenitor dependent. Developmental Cell. 2019;48:32–48. doi: 10.1016/j.devcel.2018.11.034. PubMed DOI PMC

North HA, Karim A, Jacquin MF, Donoghue MJ. EphA4 is necessary for spatially selective peripheral somatosensory topography. Developmental Dynamics. 2010;239:630–638. doi: 10.1002/dvdy.22185. PubMed DOI PMC

Oh WJ, Gu C. Establishment of neurovascular congruency in the mouse whisker system by an independent patterning mechanism. Neuron. 2013;80:458–469. doi: 10.1016/j.neuron.2013.09.005. PubMed DOI PMC

Ouspenskaia T, Matos I, Mertz AF, Fiore VF, Fuchs E. WNT-SHH antagonism specifies and expands stem cells prior to niche formation. Cell. 2016;164:156–169. doi: 10.1016/j.cell.2015.11.058. PubMed DOI PMC

Reddy S, Andl T, Bagasra A, Lu MM, Epstein DJ, Morrisey EE, Millar SE. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mechanisms of Development. 2001;107:69–82. doi: 10.1016/S0925-4773(01)00452-X. PubMed DOI

Sandor B, Fintor K, Felszeghy S, Juhasz T, Reglodi D, Mark L, Kiss P, Jungling A, Fulop BD, Nagy AD, Hashimoto H, Zakany R, Nagy A, Tamas A. Structural and morphometric comparison of the molar teeth in pre-eruptive developmental stage of PACAP-deficient and wild-type mice. Journal of Molecular Neuroscience. 2014;54:331–341. doi: 10.1007/s12031-014-0392-6. PubMed DOI

Schwarz Q, Vieira JM, Howard B, Eickholt BJ, Ruhrberg C. Neuropilin 1 and 2 control cranial gangliogenesis and axon guidance through neural crest cells. Development. 2008a;135:1605–1613. doi: 10.1242/dev.015412. PubMed DOI PMC

Schwarz Q, Waimey KE, Golding M, Takamatsu H, Kumanogoh A, Fujisawa H, Cheng HJ, Ruhrberg C. Plexin A3 and plexin A4 convey semaphorin signals during facial nerve development. Developmental Biology. 2008b;324:1–9. doi: 10.1016/j.ydbio.2008.08.020. PubMed DOI PMC

Sennett R, Rendl M. Mesenchymal-epithelial interactions during hair follicle morphogenesis and cycling. Seminars in Cell & Developmental Biology. 2012;23:917–927. doi: 10.1016/j.semcdb.2012.08.011. PubMed DOI PMC

Sennett R, Wang Z, Rezza A, Grisanti L, Roitershtein N, Sicchio C, Mok KW, Heitman NJ, Clavel C, Ma’ayan A, Rendl M. An integrated transcriptome atlas of embryonic hair follicle progenitors, their niche, and the developing skin. Developmental Cell. 2015;34:577–591. doi: 10.1016/j.devcel.2015.06.023. PubMed DOI PMC

Stainier DY, Gilbert W. Pioneer neurons in the mouse trigeminal sensory system. PNAS. 1990;87:923–927. doi: 10.1073/pnas.87.3.923. PubMed DOI PMC

Tachibana R, Tatehara S, Kumasaka S, Tokuyama R, Satomura K. Effect of melatonin on human dental papilla cells. International Journal of Molecular Sciences. 2014;15:17304–17317. doi: 10.3390/ijms151017304. PubMed DOI PMC

Taniguchi M, Yuasa S, Fujisawa H, Naruse I, Saga S, Mishina M, Yagi T. Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron. 1997;19:519–530. doi: 10.1016/s0896-6273(00)80368-2. PubMed DOI

Ulupinar E, Datwani A, Behar O, Fujisawa H, Erzurumlu R. Role of semaphorin III in the developing rodent trigeminal system. Molecular and Cellular Neurosciences. 1999;13:281–292. doi: 10.1006/mcne.1999.0747. PubMed DOI PMC

Van Exan RJ, Hardy MH. A spatial relationship between innervation and the early differentiation of vibrissa follicles in the embryonic mouse. Journal of Anatomy. 1980;131:643–656. PubMed PMC

Weil M, Itin A, Keshet E. A role for mesenchyme-derived tachykinins in tooth and mammary gland morphogenesis. Development. 1995;121:2419–2428. doi: 10.1242/dev.121.8.2419. PubMed DOI

Wrenn JT, Wessells NK. The early development of mystacial vibrissae in the mouse. Development. 1984;83:137–156. doi: 10.1242/dev.83.1.137. PubMed DOI

Wu Z, Zhu Y, Liu H, Liu G, Li F. Wnt10b promotes hair follicles growth and dermal papilla cells proliferation via Wnt/β-Catenin signaling pathway in Rex rabbits. Bioscience Reports. 2020;40:BSR20191248. doi: 10.1042/BSR20191248. PubMed DOI PMC

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, Feng T, Zhou L, Tang W, Zhan L, Fu X, Liu S, Bo X, Yu G. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation. 2021;2:100141. doi: 10.1016/j.xinn.2021.100141. PubMed DOI PMC

Yang JW, Kilb W, Kirischuk S, Unichenko P, Stüttgen MC, Luhmann HJ. Development of the whisker-to-barrel cortex system. Current Opinion in Neurobiology. 2018;53:29–34. doi: 10.1016/j.conb.2018.04.023. PubMed DOI

Zappia L, Oshlack A. Clustering trees: a visualization for evaluating clusterings at multiple resolutions. GigaScience. 2018;7:giy083. doi: 10.1093/gigascience/giy083. PubMed DOI PMC

Zhang Y, Tomann P, Andl T, Gallant NM, Huelsken J, Jerchow B, Birchmeier W, Paus R, Piccolo S, Mikkola ML, Morrisey EE, Overbeek PA, Scheidereit C, Millar SE, Schmidt-Ullrich R. Reciprocal requirements for EDA/EDAR/NF-kappaB and Wnt/beta-catenin signaling pathways in hair follicle induction. Developmental Cell. 2009;17:49–61. doi: 10.1016/j.devcel.2009.05.011. PubMed DOI PMC

Zhao H, Feng J, Seidel K, Shi S, Klein O, Sharpe P, Chai Y. Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell. 2014;14:160–173. doi: 10.1016/j.stem.2013.12.013. PubMed DOI PMC

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