HOXC8 initiates an ectopic mammary program by regulating Fgf10 and Tbx3 expression, and Wnt/β-catenin signaling

Abstract

The role of Hox genes in the formation of cutaneous accessory organs such as hair follicles and mammary glands has proved elusive, a likely consequence of overlapping function and expression among various homeobox factors. Lineage and immunohistochemical analysis of Hoxc8 in mice revealed that this midthoracic Hox gene has transient but strong regional expression in ventrolateral surface ectoderm at E10.5, much earlier than previously reported. Targeted mice were generated to conditionally misexpress Hoxc8 from the Rosa locus using select Cre drivers, which significantly expanded the domain of thoracic identity in mutant embryos. Accompanying this expansion was the induction of paired zones of ectopic mammary development in the cervical region, which generated between three and five pairs of mammary placodes anterior to the first wild-type mammary rudiment. These rudiments expressed the mammary placode markers Wnt10b and Tbx3 and were labeled by antibodies to the mammary mesenchyme markers ERα and androgen receptor. Somitic Fgf10 expression, which is required for normal mammary line formation, was upregulated in mutant cervical somites, and conditional ablation of ectodermal Tbx3 expression eliminated all normally positioned and ectopic mammary placodes. We present evidence that Hoxc8 participates in regulating the initiation stages of mammary placode morphogenesis, and suggest that this and other Hox genes are likely to have important roles during regional specification and initiation of these and other cutaneous accessory organs.

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

“…This expression pattern likely paralleled the rapid down-regulation of Hoxd8 transcription occurring in the MB between E12.5 and E13.5. This dataset, along with previous contributions (36)(37)(38), indicates that Hox genes are differentially expressed both among the various pairs of MBs and during the development of these structures, suggesting that temporal and spatial Hox combinations may contribute to MG development and specification.…”

“…Likewise, these genes have been implicated in MG development (36)(37)(38), with Hoxc8 being one of the first markers of MP specification, where it contributes to define the number and positions where these structures will form (37). The expression of Hoxc8 is nevertheless completely abrogated by E12.5.…”

Conditional Loss of Hoxa5 Function Early after Birth Impacts on Expression of Genes with Synaptic Function

“…Strikingly, very few candidate target genes are components or essential regulators of the Wnt/β-catenin, FGF, and TGF-β/Activin/BMP signaling pathways that have been identified as downstream pathways of several HOX proteins in embryonic development, neural differentiation and tumorigenesis ( Chen et al, 2005 ; Schiedlmeier et al, 2007 ; Bami et al, 2011 ; Makki and Capecchi, 2011 ; Donaldson et al, 2012 ; Carroll and Capecchi, 2015 ; Duan et al, 2015 ; Hrycaj et al, 2015 ; Roux et al, 2015 ; Karmakar et al, 2017 ; Zhang et al, 2017 ). Moreover, except from Pcp2 (see Supplementary Table S3 , line 17), none of the already identified direct or indirect targets of HOXA5 was significantly downregulated in our analysis (e.g., Ptn, Fslt1 ) ( Sanlioglu et al, 1998 ; Chen et al, 2005 ; Boucherat et al, 2013 ).…”

A tale of two cities: The genetic mechanisms governing calvarial bone development

“…In both the CNCC‐ and the PM‐specific Ezh2 mutants, multiple Hox genes are upregulated (Dudakovic et al, ; Schwarz et al, ). Hox genes have been associated with repression of Runx2 in skull bone in vivo (Carroll & Capecchi, ; Santagati, Minoux, Ren, & Rijli, ). In addition, the SOA‐mesenchyme lacks expression of all Hox genes, resulting in a potential sensitivity to ectopic Hox gene expression.…”