A HISTOLOGIC SCREEN FOR CELL DIFFERENTIATION MUTANTS

Project: Research project

Project Details

Description

DESCRIPTION: (Applicant's Abstract) This is a proposal, in response to RFA
HD-OO-0004, to perform a histological screen for ENU-induced mutations causing
either organ-specific or general histological phenotypes in 7 day old
parthenogenetic haif-tetrad larvae of zebrafish (Danio rerio). Subgoals include
confinnation of each mutation as an inheritable trait, preliminary
characterization, and mapping of each mutation to a chromosome arm. Community
functions will include posting of mutant phenotypes on the web, and
distribution of mutants to the Zebrafish Stock Center. We expect to find
mutants with defective tissue differentiation, and to produce models for
aspects of human disease, including cancer and diseases of the eye and
gastrointestinal tract.

The motivation for the screen is the power of histologic analysis in the
characterization of pathological changes in human tissues. Hundreds of cell
types and pathological changes are distinguishable from the light microscopic
study of stained tissue sections. For example, the histological changes common
to all cancers include defects in tissue organization and in the cytological
appearance of cancer cells. A genetic dissection of these changes can be
accomplished through the generation and study of mutants with histological
phenotypes.

The experimental features of the zebrafish make it an ideal vertebrate model to
identify mutants with histological phenotypes. Each female can produce hundreds
of embryos per week at a relatively low cost. Recessive mutations carried by
females may be unmasked in parthenogenetic half-tetrad progeny. A pilot
histologic screen 01 half-tetrad families of 72 carrier females produced two
mutations affecting the neural retina, two affecting the gastrointestinal
tract, and two with multi-organ effects (Cheng et al.,submitted). One mutant
showed a strong cytological phenotype in multiple organs that would be
diagnostic of severe atypia or cancer in a human cytology specimen. The
screen's success establishes the ability of this laboratory to perform all
required steps in the proposed screen, including mutagenesis, parthenogenesis,
histologic screening, and mapping. This project will contribute to an
elucidation of both organ-specific and general pathways of cell differentiation
in vertebrates.
StatusFinished
Effective start/end date4/19/013/31/07

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $384,750.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $419,750.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $384,750.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $384,750.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $384,750.00

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