Interfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours.

Epithelial cancer constitutes a major clinical challenge and molecular mechanisms underlying the process of tumour initiation are not well understood. Here we demonstrate that hair follicle bulge stem cells (SCs) give rise to well-differentiated sebaceous tumours and show that SCs are not only crucial in tumour initiation, but are also involved in tumour plasticity and heterogeneity. Our findings reveal that SC-specific expression of mutant Lef1, which mimics mutations found in human sebaceous tumours, drives sebaceous tumour formation. Mechanistically, we demonstrate that mutant Lef1 abolishes p53 activity in SCs. Intriguingly, mutant Lef1 induces DNA damage and interferes with SC-specific gatekeeper functions normally protecting against accumulations of DNA lesions and cell loss. Thus, normal control of SC proliferation is disrupted by mutant Lef1, thereby allowing uncontrolled propagation of tumour-initiating SCs. Collectively, these findings identify underlying molecular and cellular mechanisms of tumour-initiating events in tissue SCs providing a potential target for future therapeutic strategies.

A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis.

The development of the dentate gyrus is characterized by distinct phases establishing a durable stem-cell pool required for postnatal and adult neurogenesis. Here, we report that Bcl11b/Ctip2, a zinc finger transcription factor expressed in postmitotic neurons, plays a critical role during postnatal development of the dentate gyrus. Forebrain-specific ablation of Bcl11b uncovers dual phase-specific functions of Bcl11b demonstrated by feedback control of the progenitor cell compartment as well as regulation of granule cell differentiation, leading to impaired spatial learning and memory in mutants. Surprisingly, we identified Desmoplakin as a direct transcriptional target of Bcl11b. Similarly to Bcl11b, postnatal neurogenesis and granule cell differentiation are impaired in Desmoplakin mutants. Re-expression of Desmoplakin in Bcl11b mutants rescues impaired neurogenesis, suggesting Desmoplakin to be an essential downstream effector of Bcl11b in hippocampal development. Together, our data define an important novel regulatory pathway in hippocampal development, by linking transcriptional functions of Bcl11b to Desmoplakin, a molecule known to act on cell adhesion.

Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development.

Dorsal spinal cord neurons receive and integrate somatosensory information provided by neurons located in dorsal root ganglia. Here we demonstrate that dorsal spinal neurons require the Krüppel-C(2)H(2) zinc-finger transcription factor Bcl11a for terminal differentiation and morphogenesis. The disrupted differentiation of dorsal spinal neurons observed in Bcl11a mutant mice interferes with their correct innervation by cutaneous sensory neurons. To understand the mechanism underlying the innervation deficit, we characterized changes in gene expression in the dorsal horn of Bcl11a mutants and identified dysregulated expression of the gene encoding secreted frizzled-related protein 3 (sFRP3, or Frzb). Frzb mutant mice show a deficit in the innervation of the spinal cord, suggesting that the dysregulated expression of Frzb can account in part for the phenotype of Bcl11a mutants. Thus, our genetic analysis of Bcl11a reveals essential functions of this transcription factor in neuronal morphogenesis and sensory wiring of the dorsal spinal cord and identifies Frzb, a component of the Wnt pathway, as a downstream acting molecule involved in this process.

TCF/Lef1 activity controls establishment of diverse stem and progenitor cell compartments in mouse epidermis.

Mammalian epidermis consists of the interfollicular epidermis, hair follicles (HFs) and associated sebaceous glands (SGs). It is constantly renewed by stem and progenitor cell populations that have been identified and each compartment features a distinct mechanism of cellular turnover during renewal. The functional relationship between the diverse stem cell (SC) pools is not known and molecular signals regulating the establishment and maintenance of SC compartments are not well understood. Here, we performed lineage tracing experiments to demonstrate that progeny of HF bulge SCs transit through other SC compartments, suggesting a hierarchy of competent multipotent keratinocytes contributing to tissue renewal. The bulge was identified as a bipotent SC compartment that drives both cyclic regeneration of HFs and continuous renewal of SGs. Our data demonstrate that aberrant signalling by TCF/Lef1, transcription factors crucial for bulge SC activation and hair differentiation, results in development of ectopic SGs originating from bulge cells. This process of de novo SG formation is accompanied by the establishment of new progenitor niches. Detailed molecular analysis suggests the recapitulation of steps of tissue morphogenesis.