This explosive use, however, does not necessarily reflect the occurrence rate of at-risk pregnancies, and in fact one study by You et al. rise to a heterogenetic group of conditions such as autism. and studies have exhibited increased rates of mitosis, due largely to a briefer respite at G1 phase, and increased production of infragranular neurons and intermediate progenitors, possibly indicating prolonged maintenance of radial glial proliferation [49, 50]. Even though there have been reports of microcephaly in FXS particularly Vortioxetine in adult females with Rabbit Polyclonal to POU4F3 the condition, overproliferation of certain progenitor and neuronal subsets may Vortioxetine ultimately link FXS to neocortical development in idiopathic Vortioxetine autism and make some sense of the common behavioral phenotype which exists between the two [51]. When considering the molecular theme which slowly begins to develop upon closer investigation of various forms of single-gene autism, and in viewing some of the microscopic and gross morphometrical commonalities that these conditions share with the idiopathic condition, one might hypothesize that at the molecular level the broader autism can be defined by abnormal activation, specifically overactivation, Vortioxetine of the growth pathways which are common to both mitosis and neuronal arborization. However, whether overproliferation during neurogenesis is a requisite for development of the conditions, is a common yet not a mandatory predisposing factor, or it plays a coincident, minor role in ultimate phenotype due to the pathways it shares in common with neuritogenesis and synaptogenesis is still to be determined. The role of -catenin in corticogenesis and synaptogenesis -catenin is a protein intimately involved in both cell-cell adhesion and transcription. In adhesion of epithelial cells, -catenin acts as one of a set of adaptor proteins which anchors the actin cytoskeleton to the intracellular portion of E-cadherin [29]. Anchoring of the cytoskeleton in turn inhibits the treadmilling of that filament, stabilizing it [52]. Through formation of the cadherin/-catenin/-catenin/vinculin complex, p120 is recruited to E-cadherin, linking the adherens junction to several intracellular signaling pathways such as various receptor tyrosine kinases (RTK) [53]. The extracellular portion of E-cadherin, upon activation, binds an identical extracellular portion of another E-cadherin in an adjacent epithelial cell, enabling cells to communicate information to their neighbors regarding the state of their cytoskeletal structures. This ultimately can facilitate the coordinated migration, adhesion, and differentiation of adjacent cells. In the case of transcription within epithelia, cytosolic -catenin is normally phosophorylated Vortioxetine by both CK1 and GSK3 of the Axin/APC complex and thereby marked for degradation; however, upon canonical Wnt activation -catenin is freed into the cytosol and is transferred into the nucleus via transporters such as Pygopus and BCL9. Incidentally, anything which downregulates, deactivates, or sequesters GSK3 away from the Axin/APC complex will subsequently upregulate cytosolic -catenin levels. Once within the nucleus, -catenin binds LEF/TCF to stimulate transcription of Wnt target genes [54]. All forms of -catenin, despite their different localizations, are transcribed from the same gene; therefore, distinctions in molecular form and function are thought to be achieved through variations in phosphorylation, binding partners, and cleavage along the arm domain of the protein. It is suspected that binding may enhance the negative charge along -catenins positive groove, increasing binding affinity for certain partners dependent upon the precise site or sites phosphorylated. Changes in E-cadherin phosphorylation can also affect -catenin binding to the adherens complex [43]. As mentioned, -catenin plays a vital role in both epithelial adhesion and Wnt-targeted transcription. The Wnt family is a highly conserved set of extracellular signaling molecules which are intimately involved in embryonic development. Canonical Wnt has both direct and indirect gene targets which it activates and which also may cyclically regulate the Wnt pathway. As mentioned earlier, direct targets include genes such as cyclin D1, necessary for G1-to-S phase progression during mitosis, and MYC, a transcription factor which is believed to act as an enhancer for up to 15% of all genes [55, 56, 57]. (For a listing of both direct and indirect targets of Wnt activation, see [58].) However, while -catenin activation is a prerequisite for transcription of cyclin D1 and MYC and therefore growth and division of totipotent and multipotent cells, canonical Wnt activation is not the only method by.