Biomedical subjects

Elizabeth P Murchison

Publications and source records attributed to Elizabeth P Murchison.

4 recordsLinked to original sources

PubMed2006

The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles.

The discovery that microRNAs (miRNAs) play important roles in regulating gene expression via posttranscriptional repression has revealed a previously unsuspected mechanism controlling development and progenitor-cell function (reviewed in ); however, little is known of miRNA functions in mammalian organogenesis. Processing of miRNAs and their assembly into the RNA-induced silencing (RISC) complex requires the essential multifunctional enzyme Dicer . We found that Dicer mRNA and multiple miRNAs are expressed in mouse skin, suggesting roles in skin- and hair-follicle biology. In newborn mice carrying an epidermal-specific Dicer deletion, hair follicles were stunted and hypoproliferative. Hair-shaft and inner-root-sheath differentiation was initiated, but the mutant hair follicles were misoriented and expression of the key signaling molecules Shh and Notch1 was lost by postnatal day 7. At this stage, hair-follicle dermal papillae were observed to evaginate, forming highly unusual structures within the basal epidermis. Normal hair shafts were not produced in the Dicer mutant, and the follicles lacked stem cell markers and degenerated. In contrast to decreased follicular proliferation, the epidermis became hyperproliferative. These results reveal critical roles for Dicer in the skin and implicate miRNAs in key aspects of epidermal and hair-follicle development and function.

Animals↗

PubMed2005

Characterization of Dicer-deficient murine embryonic stem cells.

Dicer is an RNase III-family nuclease that initiates RNA interference (RNAi) and related phenomena by generation of the small RNAs that determine the specificity of these gene silencing pathways. We have previously shown that Dicer is essential for mammalian development, with Dicer-deficient mice dying at embryonic day 7.5 with a lack of detectable multipotent stem cells. To permit a more detailed investigation of the biological roles of Dicer, we have generated embryonic stem cell lines in which their single Dicer gene can be conditionally inactivated. As expected, Dicer loss compromises maturation of microRNAs and leads to a defect in gene silencing triggered by long dsRNAs. However, the absence of Dicer does not affect the ability of small interfering RNAs to repress gene expression. Of interest, Dicer loss does compromise the proliferation of ES cells, possibly rationalizing the phenotype previously observed in Dicer-null animals. Dicer loss also affects the abundance of transcripts from mammalian centromeres but does so without a pronounced affect on histone modification status at pericentric repeats or methylation of centromeric DNA. These studies provide a conditional model of RNAi deficiency in mammals that will permit the dissection of the biological roles of the RNAi machinery in cultured mammalian cells.

Animals↗

PubMed2004

miRNAs on the move: miRNA biogenesis and the RNAi machinery.

Recent advances have led to a more detailed understanding of RNA interference and its role in microRNA biogenesis and function. Primary microRNA transcripts are processed by the RNaseIII nuclease, Drosha, and are exported from the nucleus by Exportin-5. Dicer cleaves microRNAs into their mature forms, which can be incorporated into effector complexes that mediate gene silencing activities. The 3' two-nucleotide overhang structure, a signature of RNaseIII cleavage, has been identified as a critical specificity determinant in targeting and maintaining small RNAs in the RNA interference pathway. MicroRNA functional analyses and genetic and biochemical interrogation of components of the pathway are starting to provide a glimpse at the range of biological processes and phenomena regulated by RNA interference.

Animals↗

PubMed2003

Dicer is essential for mouse development.

To address the biological function of RNA interference (RNAi)-related pathways in mammals, we disrupted the gene Dicer1 in mice. Loss of Dicer1 lead to lethality early in development, with Dicer1-null embryos depleted of stem cells. Coupled with our inability to generate viable Dicer1-null embryonic stem (ES) cells, this suggests a role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development.

Amino Acid Sequence↗