Author
Heather L. Alcorn
Other affiliations: Memorial Sloan Kettering Cancer Center
Bio: Heather L. Alcorn is an academic researcher from Kettering University. The author has contributed to research in topics: Gastrulation & Morphogenesis. The author has an hindex of 8, co-authored 11 publications receiving 2401 citations. Previous affiliations of Heather L. Alcorn include Memorial Sloan Kettering Cancer Center.
Papers
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TL;DR: A role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development is suggested.
Abstract: 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.
1,966 citations
TL;DR: This work has identified recessive ENU-induced mutations in six genes that prevent normal specification of ventral cell types in the spinal cord, and positionally cloned the genes responsible for two of the mutant phenotypes, smoothened and dispatched, which are homologs of Drosophila Hh pathway components.
192 citations
TL;DR: In this paper, a forward genetic approach was used to induce recessive mutations by treatment of mice with ethylnitrosourea and identified 43 mutations that affect early morphogenesis and patterning, including 38 genes that have not been studied previously.
Abstract: Many aspects of the genetic control of mammalian embryogenesis cannot be extrapolated from other animals. Taking a forward genetic approach, we have induced recessive mutations by treatment of mice with ethylnitrosourea and have identified 43 mutations that affect early morphogenesis and patterning, including 38 genes that have not been studied previously. The molecular lesions responsible for 14 mutations were identified, including mutations in nine genes that had not been characterized previously. Some mutations affect vertebrate-specific components of conserved signaling pathways; for example, at least five mutations affect previously uncharacterized regulators of the Sonic hedgehog (Shh) pathway. Approximately half of all of the mutations affect the initial establishment of the body plan, and several of these produce phenotypes that have not been described previously. A large fraction of the genes identified affect cell migration, cellular organization, and cell structure. The findings indicate that phenotype-based genetic screens provide a direct and unbiased method to identify essential regulators of mammalian development.
137 citations
TL;DR: Deletion of the BMP receptor genes in the mouse telencephalon results in a loss of all dorsal midline cell types without affecting the specification of cortical and ventral precursors, suggesting that two separate developmental mechanisms can underlie the ontogeny of HPE.
Abstract: Holoprosencephaly (HPE) is a devastating forebrain abnormality with a range
of morphological defects characterized by loss of midline tissue. In the
telencephalon, the embryonic precursor of the cerebral hemispheres,
specialized cell types form a midline that separates the hemispheres. In the
present study, deletion of the BMP receptor genes, Bmpr1b and
Bmpr1a, in the mouse telencephalon results in a loss of all dorsal
midline cell types without affecting the specification of cortical and ventral
precursors. In the holoprosencephalic Shh-/- mutant, by
contrast, ventral patterning is disrupted, whereas the dorsal midline
initially forms. This suggests that two separate developmental mechanisms can
underlie the ontogeny of HPE. The Bmpr1a;Bmpr1b mutant
provides a model for a subclass of HPE in humans: midline inter-hemispheric
HPE.
102 citations
TL;DR: The results indicate that although increased stability of Axin2 leads to a loss of canonical Wnt signaling in most tissues, stabilized Axin 2 enhances Wnt pathway activity in a specific progenitor population in the late primitive streak.
Abstract: Axin proteins are key negative regulators of the canonical Wnt signal transduction pathway. Although Axin2 null mice are viable, we identified an unusual ENU-induced recessive allele of Axin2, canp, that causes midgestation lethality in homozygotes. We show that the Axin2canp mutation is a V26D substitution in an invariant N-terminal sequence motif and that the Axin2canp protein is more stable than wild type. As predicted for an increased level of a negative regulator, the Axin2canp mutation leads to decreased Wnt signaling in most tissues, and this can account for most of the morphological phenotypes of Axin2canp mutants. In contrast, there is a paradoxical increase in canonical Wnt activity in the late primitive streak of all Axin2canp mutant embryos that is associated with the formation of an ectopic tail in some mutants. Treatment of wild-type embryos with an inhibitor of Tankyrase that stabilizes Axin proteins also causes inhibition of Wnt signaling in anterior regions of the embryo and a gain of Wnt signaling in the primitive streak. The results indicate that although increased stability of Axin2 leads to a loss of canonical Wnt signaling in most tissues, stabilized Axin2 enhances Wnt pathway activity in a specific progenitor population in the late primitive streak.
51 citations
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TL;DR: Two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events and indicate the existence of multiple RISCs that carry out related but specific biological functions.
Abstract: MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.
6,282 citations
Journal Article•
TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
Abstract: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
6,064 citations
TL;DR: Evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes.
Abstract: MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer
5,693 citations
TL;DR: Small non-coding RNAs that function as guide molecules in RNA silencing are involved in nearly all developmental and pathological processes in animals and their dysregulation is associated with many human diseases.
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, and their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are ∼22 nucleotides in length, and they are produced by two RNase III proteins--Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non-canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging.
4,256 citations
TL;DR: Recent advances in knowledge of the microRNA biosynthesis pathways are reviewed and their impact on post-transcriptional microRNA regulation during tumour development is discussed.
Abstract: MicroRNAs are important regulators of gene expression that control both physiological and pathological processes such as development and cancer. Although their mode of action has attracted great attention, the principles governing their expression and activity are only beginning to emerge. Recent studies have introduced a paradigm shift in our understanding of the microRNA biogenesis pathway, which was previously believed to be universal to all microRNAs. Maturation steps specific to individual microRNAs have been uncovered, and these offer a plethora of regulatory options after transcription with multiple proteins affecting microRNA processing efficiency. Here we review the recent advances in knowledge of the microRNA biosynthesis pathways and discuss their impact on post-transcriptional microRNA regulation during tumour development.
2,561 citations