Long-range genomic rearrangements upstream of Kit dysregulate the developmental pattern of Kit expression in W57 and W(banded) mice and interfere with distinct steps in melanocyte development

Michael Klüppel, Deborah L. Nagle, Maja Bucan, Alan Bernstein*

*Corresponding author for this work

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Mutations in the murine dominant white spotting (W) locus cause pleiotropic developmental defects that affect hematopoietic cells, melanocytes, germ cells and the interstitial cells of Cajal in the gut. W mutations either alter the coding sequence of the Kit receptor tyrosine kinase, resulting in a receptor with impaired kinase activity, or affect Kit expression. Here we describe the molecular and cell-type-specific developmental defects of two of the latter class of regulatory W alleles, W57 and W(banded(bd)). In both mutants, the temporal and spatial patterns of Kit expression are dysregulated during embryogenesis and in adult animals. In W(bd) mice, ectopic expression of Kit in the dermatome of the somites at days 10.8 and 11.8 of development seemed to interfere with melanoblast development. In contrast, the W57 allele leads to an intrinsic pigmentation defect by downregulating developmental Kit expression in trunk melanoblasts, but not melanoblasts around the otic vesicle. Both mutations affect transcriptional initiation of the Kit gene. The W57 allele is associated with a 80 kb deletion 5' of the Kit-coding region while W(bd) is associated with a 2.8 Mb genomic inversion of chromosome 5 with the distal breakpoint between Kit and the platelet-derived growth factor receptor alpha (Pdgfra) gene, and the proximal breakpoint between the genes for the GABA receptor beta 1 (Gabrb1) and the Tec tyrosine kinase, juxtaposing the Kit and Tee tyrosine kinase genes: Neither W57 nor W(bd) affect genomic sequences previously suggested in in vitro experiments to control cell-type-specific expression of Kit. These results link specific mechanisms of cellular and developmental defects to long-range genomic rearrangements that positively and negatively affect Kit transcription in different cell lineages as well as in different subpopulations of the same lineage.

Original languageEnglish (US)
Pages (from-to)65-77
Number of pages13
JournalDevelopment
Volume124
Issue number1
StatePublished - Jan 1997

Keywords

  • Dominant white spotting
  • Genomic rearrangement
  • Kit
  • Melanocyte
  • Melanogenesis
  • Mouse
  • Steel
  • Transcriptional regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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