Decrease, SHH second messenger production leads to Decrease, Cell proliferation

SHH is a mitogen that regulates cell proliferation during development. SHH regulation of proliferation works at least in part through regulation of cyclin D1 (ccnd 1) and cyclin D2 (Ccnd 2) (Kenney and Rowitch 2000, Ishibashi and McMahon 2002, Lobjois, Benazeraf et al. 2004, Mill, Mo et al. 2005, Hu, Mo et al. 2006). The regulation of ccnd 1 and ccnd 2 by SHH is not fully understood but is believed to be in part by regulation via SHH signaling and its signaling to SHH secondary messengers, namely the fibroblast growth factor family. A network of reciprocal growth factor signaling between the epithelium and mesenchyme is required for proper growth and patterning of the early palatal shelves. This signaling is largely comprised of a network between bone morphogenic protein (BMP), Fibroblast growth factor (Fgf), and Sonic Hedgehog (SHH) (Zhang, Song et al. 2002, Rice, Spencer-Dene et al. 2004). Activation of the SHH pathway results in a downstream signaling cascade resulting in the relocation of GLI to the nucleus and subsequent gene transcription (Carballo, Honorato et al. 2018). This gene expression drives secondary messenger signaling for the pathway. Proper Msx1 activity in the mesenchyme is required for the expression of SHH in the overlying epithelium (Zhang, Song et al. 2002). Maintenance of SHH expression in the epithelium is believed to be dependent on Fgf10 expression in the mesenchyme and its’ signaling through Fgfr2b in the epithelium (Rice, Spencer-Dene et al. 2004). 

          Pubmed was used as the primary database for evidence collection. Searches are organized by the date and search terms used in the supplementary table. Search results were initially screened through review of the title and abstract for potential for data relating SHH signaling and secondary messengers and SHH cellular proliferation. Each selected publication and its’ data were then examined to determine if support or lack thereof existed for this KER. Papers that did not show any data relating to this KER were discarded. The search terms used are organized below in Table 1.

Table 1: KER 2732 literature search

The quantitative understanding of this relationship is low. No studies were found to exist to address dose response or time-scale data. Further work is needed to address these questions and create a better understanding of this relationship.

The relationship between a decrease in SHH secondary messengers and a decrease in cellular proliferation translocation has been demonstrated in both mouse and chick models. The relationship is biologically plausible in human, but to date no specific experiments have addressed this question. The SHH pathway is well understood to be fundamental to proper embryonic development and that aberrant SHH signaling during embryonic development can cause birth defects including orofacial clefts (OFCs). For this reason, this KER is applicable to the embryonic stage with a high level of confidence.