Project description:The hair follicle misorientation phenotype in Fzd6-/- mice appears to act through the PCP signaling system, but the downstream effectors of Fzd6 remain mysterious. We used microarrays to search for potential downstream effectors of the Fzd6 signaling pathway in regulating hair follicle orientation.
Project description:The exogen phase of the hair follicle cycle, during which club hairs are shed and new hairs emerge, represents a pivotal yet understudied transition marked by structural remodeling and cell fate changes. This study investigates the role of the transcription factor Msx2 in regulating hair anchoring, hair follicle stem cell (HFSC) lineage commitment, and extracellular matrix (ECM) remodeling during exogen. Using Msx2-knockout (KO) mice, we integrated transcriptomic, epigenomic, and functional assays to reveal Msx2 as a key regulator of exogen, critical for maintaining HFSC niche integrity, preserving bulge architecture, and coordinating lineage progression during hair regeneration. By modulating the balance between TGF-β and Wnt signaling pathways, Msx2 ensures proper HFSC activation and prevents premature epidermal differentiation and hair shedding. These findings provide mechanistic insights into the molecular control of hair cycling and highlight Msx2 dysfunction as a potential contributor to hair loss disorders, positioning it as a promising therapeutic target in regenerative dermatology.
Project description:The exogen phase of the hair follicle cycle, during which club hairs are shed and new hairs emerge, represents a pivotal yet understudied transition marked by structural remodeling and cell fate changes. This study investigates the role of the transcription factor Msx2 in regulating hair anchoring, hair follicle stem cell (HFSC) lineage commitment, and extracellular matrix (ECM) remodeling during exogen. Using Msx2-knockout (KO) mice, we integrated transcriptomic, epigenomic, and functional assays to reveal Msx2 as a key regulator of exogen, critical for maintaining HFSC niche integrity, preserving bulge architecture, and coordinating lineage progression during hair regeneration. By modulating the balance between TGF-β and Wnt signaling pathways, Msx2 ensures proper HFSC activation and prevents premature epidermal differentiation and hair shedding. These findings provide mechanistic insights into the molecular control of hair cycling and highlight Msx2 dysfunction as a potential contributor to hair loss disorders, positioning it as a promising therapeutic target in regenerative dermatology.
Project description:Posttranslational protein modifications have emerged as a mechanism regulating progenitor cell state transitions during tissue formation. Herein, we exploit the stereotyped hair follicle development to delineate the function of PADI4; an enzyme converting peptidylarginine to citrulline. Single cell-sequencing places Padi4 in both progenitor and differentiated hair lineage cells and indicate that PADI4 acts to repress transcription during hair follicle development. We establish PADI4 as a negative regulator of proliferation, acting on LEF1-positive hair shaft committed progenitor cells. Mechanistically, PADI4 citrullinates proteins associated with mRNA-processing and ribosomal biogenesis, and lack of PADI4 promotes protein synthesis and rRNA transcription in vivo. Characterizing key translational effectors, we demonstrate that PADI4 citrullinates the translational repressor 4E-BP1 and reveal a crosstalk between PADI4 activity and 4E-BP1 phosphorylation. This work sheds new light on how posttranslational modifications impact progenitor cell states and tissue formation.
Project description:Dermal lymphatics form a network that connects all the hair follicles in skin and localize in proximity to the Hair Follicle Stem Cell. RNA sequencing analyses of isolated dermal lymphatics at two different time points of the hair follicle cycle (P55 and P70) indicate the existence of dynamic signaling networks associated with lymphatic remodeling, immune trafficking, and HF signaling.
Project description:Tissue formation requires a coordinated balance of progenitor cell proliferation and differentiation. Posttranslational protein modifications have emerged as a mechanism utilized to regulate progenitor cell state transitions. Herein, we exploit the well characterized and stereotyped hair follicle development to delineate the function of PADI4; an enzyme converting peptidylarginine to citrulline. Single cell-sequencing places Padi4 in both progenitor and differentiated hair lineage cells during hair follicle development. We show that the absence of PADI4 induces gene expression across hair follicle cell clusters, suggesting that PADI4 acts to negatively impact transcription. In addition, we establish PADI4 as a negative regulator of proliferation, acting of LEF1-positive hair shaft committed progenitor cells. Mechanistically, PADI4 citrullinates proteins associated with mRNA-processing and ribosomal biogenesis, and lack of PADI4 promotes protein synthesis and rRNA transcription in vivo, in both hair follicle progenitor and committed lineage cells. Characterizing key translational effectors, we demonstrate that PADI4 interacts with 4E-BP1 and reveal a crosstalk between PADI4 activity and 4E-BP1 phosphorylation. We report that PADI4 contributes to hair follicle development by repressing progenitor cell proliferation and translational activity. This work sheds new light on how posttranslational modifications impact progenitor cell states and tissue formation.
Project description:Stem cells upended from their niche upon injury display lineage plasticity, a transient multi-lineage state essential for tissue repair. Employing high-throughput approaches and three-dimensional cultures of hair follicle stem cells (HFSCs), we investigate the signals that govern the transition between homeostatic regeneration and lineage plasticity. We identify retinoic acid (RA) as a master orchestrator of HFSC behavior during these two processes. In the hair follicle, RA signals within defined niches and interacts with WNT and BMP cues to drive hair regeneration. In wounded skin, reduced RA signaling prompts HFSCs to prioritize epidermal re-epithelialization and must be restored to promote hair regrowth. Substantiated in vivo, our findings have profound therapeutic implications for hair growth and for chronic wounds and cancers, where lineage plasticity is unresolved.