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Modeling Neuroretinal Development and Disease in Stem Cells
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Antagonizing both Wnt and BMP signaling also seems important for eye development. Dickkopf1 (Dkk1) is a potent antagonist of canonical Wnt signaling, and mice carrying null deletions of Dkk1 lose all cranial structures anterior to the midbrain, including the eyes (Mukhopadhyay et al., 2001). Noggin (Nog), a known inhibitor of BMP signaling, is believed to play an important role in neural induction and eye field formation (Lamb et al., 1993; Zuber et al., 2003). In animal cap assays, Nog causes increased expression of many EFTFs including Pax6, Six3, Rx, Lhx2, and Optx2 (Zuber et al., 2003). In mice, Dkk1 and Nog pathways synergize to induce head formation during gastrulation by dually antagonizing Wnt and BMP signaling, acting as a head organizer (del Barco Barrantes et al., 2003); loss of one copy each of Dkk1 and Nog also results in total loss of the anterior head. Insulin-like growth factors (IGF-1) are believed to play an important role in head and eye formations (Pera et al., 2001), and it is achieved by the inhibition of canonical Wnt signaling (Richard-Parpaillon et al., 2002) via kermit2 (Gipc1), which is both an IGF receptor- and a Frizzled receptor-interacting protein (Wu et al., 2006). Recently, work using mouse embryonic stem cells (mESCs) has confirmed the importance of the PDZ domain-containing protein GIPC PDZ domain-containing family member 1 (GIPC1) (La Torre et al., 2015). They showed that the overexpression of a dominant negative form of GIPC PDZ domain-containing family member 1 (dnGIPC1), as well as the downregulation of endogenous GIPC1, is sufficient to inhibit the development of eye field cells from mESCs. Here, GIPC1 interacts directly with IGF receptor and participates in Akt1 activation. This was confirmed by experiments where the pharmacological inhibition of Akt1 phosphorylation mimicked the dnGIPC1 phenotype. After the initial formation of the eye field, Sonic hedgehog (Shh) signaling from the midline splits the eye field to form two eyes (Chiang et al., 1996). Shh has been shown to repress Pax6 expression via ventral anterior homeobox 2 (Vax-2), a homeodomain transcription factor (Li et al., 1997; Kim and Lemke, 2006). Loss of Shh in the midline results in cyclopia, the development of a single midline eye (Chiang et al., 1996). Thus, a balance largely between Wnt and BMP signaling activations/inhibitions by localized extracellular signaling centers is crucial in regulating eye field induction and morphogenesis during early stages of development.
REDAN: relative entropy-based dynamical allosteric network model
Published in Molecular Physics, 2019
Similar with other network models [21,26], the pathway and community analyses could also be conducted in this allosteric network model. A typical allosteric pathway consists a series of edges connecting two distal residues to exhibit the potential communication between residues leading to the allosteric effects. An allosteric community represents a group of residues with minimum allosteric effects upon perturbation. The second PDZ domain (PDZ2) in the human PTP1E protein [28] is an allosteric protein which could propagate signals to other part of molecular complex upon peptide binding [28,29], and is subjected to the allosteric pathway and community analysis using REDAN method to reveal potential allosteric mechanism and identify allostery-related residues.