Mus Musculus Neural Crest Development: Is Pax3 Regulating the Expression of Endothelin Receptor B?

The vertebrate Neural Crest (NC) is formed during early embryonic development at the neurulation stage. This group of multi potent cells gives rise to a variety of derivatives such as the skin's pigmented cells (Melanocytes), the peripheral nervous system with its associated components, and the endocrine cells of the adrenal medulla amongst others. There are several molecular mechanisms that underlie the development and migration of NC derived cells. For example, during melanocyte differentiation and migration the Endothelin Receptor B and its ligand Endothelin 3 (EdnrB/Edn3), the kit/ Steel factor and the FGF receptor I FGF pathways amongst others play important roles. Additionally, several transcription factors such as Pax3, SoxlO and Mitfalso intervene during the NC cells differentiation processes. In this work, the possible regulatory interaction of Pax3 and EdnrB was assessed by in situ hybridization methods with EdnrB, SoxlO and Dct riboprobes in Pax3 homozygous embryos. To further characterize this interaction, genetic crosses between Pax3 heterozygous mutants and EdnrB heterozygous animals were established. Coat pigmentation was used as an indicator of genetic interaction on the progeny. Experimental results indicated that Pax3 does not directly regulate the expression of EdnrB during neural crest development but interact to produce normal coat color. I propose two possible models to explain the epistatic relationship of Pax3 and EdnrB during normal melanocyte development.

Reduced Androgen Receptor Expression Accelerates the Onset of ERBB2 Induced Breast Tumors in Female Mice

Androgen receptor (AR) is commonly expressed in both the epithelium of normal mammary glands and in breast cancers. AR expression in breast cancers is independent of estrogen receptor alpha (ERα) status and is frequently associated with overexpression of the ERBB2 oncogene. AR signaling effects on breast cancer progression may depend on ERα and ERBB2 status. Up to 30% of human breast cancers are driven by overactive ERBB2 signaling and it is not clear whether AR expression affects any steps of tumor progression in this cohort of patients. To test this, we generated mammary specific Ar depleted mice (MARKO) by combining the floxed allele of Ar with the MMTV-cre transgene on an MMTV-NeuNT background and compared them to littermate MMTV-NeuNT, Arfl/+ control females. Heterozygous MARKO females displayed reduced levels of AR in mammary glands with mosaic AR expression in ductal epithelium. The loss of AR dramatically accelerated the onset of MMTV-NeuNT tumors in female MARKO mice. In this report we show that accelerated MMTV-NeuNT-dependent tumorigenesis is due specifically to the loss of AR, as hormonal levels, estrogen and progesterone receptors expression, and MMTV-NeuNT expression were similar between MARKO and control groups. MMTV-NeuNT induced tumors in both cohorts displayed distinct loss of AR in addition to ERα, PR, and the pioneer factor FOXA1. Erbb3 mRNA levels were significantly elevated in tumors in comparison to normal mammary glands. Thus the loss of AR in mouse mammary epithelium accelerates malignant transformation rather than the rate of tumorigenesis.