A New Role for an Old Friend: NFAT and Stem Cell Quiescence

NFAT proteins are calcium-regulated transcription factors that play a critical role during the timing and activation of many vertebrate tissues. A recent paper in Cell (Horsley et al., 2008) demonstrates a role of the calcineurin-NFAT-CDK4 pathway in maintaining hair follicle stem cell quiescence

Hair cycle regulation of Hedgehog signal reception

AbstractProper patterning of self-renewing organs, like the hair follicle, requires exquisite regulation of growth signals. Sonic hedgehog (Shh) signaling in skin controls the growth and morphogenesis of hair follicle epithelium in part through regulating the Gli transcription factors. While ectopic induction of Shh target genes leads to hair follicle tumors, such as basal cell carcinomas, how Shh signaling normally functions during the cyclic process of hair development is unknown. Here, we show that, during the hair cycle, Shh expression and the ability of skin cells to respond to Shh signaling is spatially and temporally regulated. Induction of Shh target genes normally occurs only in the anagen hair follicle in response to expression of Shh. However, in patched1 heterozygous mice, putative tumor precursors form with concomitant induction of Shh target gene transcription only during anagen in follicular and interfollicular keratinocytes. Ectopic production of Gli1 accumulates Gli protein and induces Shh target genes and epithelial tumors at anagen but not other stages, pointing to a restricted competence occurring at the level of Gli protein accumulation. Delivery and reception of growth signals among multipotent cells are restricted in time and space to facilitate cyclic pattern formation

“Atypical” Regulation of Hedgehog-Dependent Cancers

Growing evidence indicates targeting PKCι may be effective in treating Hedgehog-dependent cancers. In this issue of Cancer Cell, Justilien and colleagues present the surprising finding that PKCι promotes Hedgehog ligand production and lung squamous cell carcinoma growth through SOX2, rather than the canonical transcription factor GLI

“Patch”ing Up Our Tumor Signaling Knowledge

The tumor suppressor Patched1 (Ptch1) possesses well-described roles in regulating sonic hedgehog (SHH) signaling in the skin and preventing the formation of basal cell carcinomas (BCCs). In this issue, Kang et al. extend their previous work to show that a naturally occurring allele of Ptch1 found in FVB mice promotes early squamous cell carcinoma (SCC) growth without aberrant activation of the SHH pathway. The study reveals new roles for Ptch1 that lie at the nexus between BCC and SCC formation

Receptor tyrosine phosphatase–dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4

During development, dynamic remodeling of the actin cytoskeleton allows the precise placement and morphology of tissues. Morphogens such as Sonic hedgehog (Shh) and local cues such as receptor protein tyrosine phosphatases (RPTPs) mediate this process, but how they regulate the cytoskeleton is poorly understood. We previously identified Basal cell carcinoma–enriched gene 4 (BEG4)/Missing in Metastasis (MIM), a Shh-inducible, Wiskott-Aldrich homology 2 domain–containing protein that potentiates Gli transcription (Callahan, C.A., T. Ofstad, L. Horng, J.K. Wang, H.H. Zhen, P.A. Coulombe, and A.E. Oro. 2004. Genes Dev. 18:2724–2729). Here, we show that endogenous MIM is induced in a patched1-dependent manner and regulates the actin cytoskeleton. MIM functions by bundling F-actin, a process that requires self-association but is independent of G-actin binding. Cytoskeletal remodeling requires an activation domain distinct from sequences required for bundling in vitro. This domain associates with RPTPδ and, in turn, enhances RPTPδ membrane localization. MIM-dependent cytoskeletal changes can be inhibited using a soluble RPTPδ-D2 domain. Our data suggest that the hedgehog-responsive gene MIM cooperates with RPTP to induce cytoskeletal changes

Laminin-511 and integrin beta-1 in hair follicle development and basal cell carcinoma formation

<p>Abstract</p> <p>Background</p> <p>Initiation of the hair follicle placode and its subsequent growth, maturation and cycling in post-natal skin requires signaling interactions between epithelial cells and adjacent dermal cells and involves Shh signaling via the primary cilium. Previous reports have implicated laminins in hair follicle epithelial invagination.</p> <p>Results</p> <p>Here we use a human BCC model system and mouse mutants to re-evaluate the role of laminin-511 in epithelial invagination in the skin. Blocking laminin 511 and 332 in BCCs maintains primary cilia and Shh signalling, but prevents invagination. Similarly, in laminin-511 and dermal beta-1 integrin mutants, dermal papilla development and primary cilia formation are normal. Dermal beta-1 integrin mutants have normal hair follicle development.</p> <p>Conclusions</p> <p>Our data provides support for a primary role of laminin-511 promoting hair follicle epithelial downgrowth without affecting dermal primary cilia and Shh target gene induction.</p

MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression

I-BAR protein antagonism of endocytosis mediates directional sensing during guided cell migration

The I-BAR domain–containing protein, missing-in-metastasis, directs cell motility by opposing the endocytic activity of the endophilin–CD2AP–cortactin complex