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Insulin/IGF Signaling in Early Brain Development
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Selma Yagoub, Rachel N. Lippert
After the closure of the neural chord, the proliferation of neuronal cells occurs. This neurogenesis is mediated in part by insulin but has primarily been studied in the context of IGF signaling. Seminal studies have concentrated on the role of these peptides in neurogenesis in the chick embryonic retina. Further studies using in vitro models have confirmed the role of insulin, IGF-1 and IGF-2 as trophic factors for neurons in culture. Using cultured sympathetic neurons from 7-day-old chick embryos, insulin, IGF-1 and IGF-2 induced a significant increase in proliferation of this neuronal cell type (29). The specific action of IGF1 and IGF2 on this process was via the Insulin-like Growth Factor Binding Proteins (IGFBPs) rather than directly via receptor-mediated signaling. In primary fetal rat neuronal cells, IGF-1 increases the survival and expansion of neuronal and non-neuronal cell populations (30). Further, stimulation of growth of neural stem cells (NSCs) by other growth factors, such as EGF and FGF-2 requires the presence of IGF-1 (31). This effect is mediated by the phosphorylation of Akt/Bad/Bcl-2 signaling and the phosphorylation of Akt at Thr308 and Ser473 and is inhibited in the presence of excess PTEN, a protein phosphatase, as shown in Figure 2.1 (32, 33). The derivation of neural tissues from embryonic stem cells necessitates IGF-2 signaling via the IGF1-R and subsequent modulation of neural markers, SOX1, IRX3, and SIX3, further indicating a role of the IGF axis in neurogenesis and differentiation (34).
Regulation of the Pituitary Gland by Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The ontogeny of the anterior pituitary depends upon a progressive cascade of activated extrinsic or intrinsic transcription factors and signaling molecules. The initial extrinsic phase of murine pituitary development comprises signals emanating from both the ventral diencephalon and the oral ectoderm. As illustrated in Figure 5.8A at mouse embryonic day (E) 6.5–7, the anterior portion of the neural plate is destined to give rise to the primordial pituitary, while the adjacent midline region will become the endocrine hypothalamus [43]. At E8, the oral ectoderm starts to proliferate in response to Shh, Six3, Otx2 and Hex1 and participates in midline formation. Proliferation continues at E9 in response to Bmp4, Fgf8, Wnt2 and Nkx2 coming from the neural epithelium. At the same time, the oral ectoderm begins to invaginate upward and to form a rudimental Rathke’s pouch, which expresses Lhx3/4 and Pitx1/2. At the edge of the pouch, Bmp2 makes contact with the oral ectoderm and antagonizes Fgf2, which is expressed by the neural epithelium. Subsequently, an Bmp2–Fgf8 ventral–dorsal gradient is established that determines the activation of specific genes in each cell group according to their localization within the pouch.
Relevance of facial features in ultrasound diagnosis of Holoprosencephaly
Published in J. Belinha, R.M. Natal Jorge, J.C. Reis Campos, Mário A.P. Vaz, João Manuel, R.S. Tavares, Biodental Engineering V, 2019
B. Fernandes, I. Côrte-Real, P. Mesquita, M.H. Figueiral, P. Vaz, F. Valente
Regarding aetiology, until the date, are described seven genes involved in HPE: Sonic hedgehog (SHH), ZIC2, SIX 3, TGIF, PTCH, GLI2 and TDGF1. Currently, molecular diagnosis, by genomic sequencing and allele quantification, can be performed for the four major genes, SHH, ZIC2, SIX3 and TGIF respectively. However, it is estimated that in about 70% of cases the molecular basis of the disease remains unknown, which makes suggestive the existence of several other responsible genes or even environmental factors. The multifactorial origin assigned, resulting from the interaction of genetic and/or environmental factors (like maternal diabetes), has even been proposed to explain the wide clinical variability of HPE (Dubourg et al. 2007).
A Review on the Application of Stem Cell Secretome in the Protection and Regeneration of Retinal Ganglion Cells; a Clinical Prospect in the Treatment of Optic Neuropathies
Published in Current Eye Research, 2022
Fatemeh Sanie-Jahromi, Ahmad Mahmoudi, Mohammad Reza Khalili, M. Hossein Nowroozzadeh
The anterior extension of the neural retina is referred to as the non-pigmented ciliary epithelium. Non-pigmented ciliary epithelium cells (NPCECs) are derivatives of the neural tube and introduced as attractive candidates for cell-based neuroprotective treatments. Some studies reported that NPCEC can differentiate into amacrine cells, ganglion cells, and Müller glia.78 According to the study by Walshe et al., the NPCECs secretome induces RGC differentiation in-vitro and TGF-β1 is one of the neurotrophic factors having a pivotal role in this process.79 Bhatia et al., in an in vitro study, compared the neurogenic and proliferative abilities of Müller glia stem cells with both pigmented and non-pigmented ciliary epithelium cells. They reported that NPCECs proliferate and express neural markers but don’t differentiate into neurons; in other words, NPCECs showed limited neurogenic ability in comparison to Müller glia stem cells.80 In a review by Fischer, several retinal progenitor cells -including NPCECs- were investigated for their potential for neural regeneration in the chick retina model.81 This study showed that various growth factors, such as IGF-I, EGF, and FGF2, enhance the proliferation and differentiation of neural progenitors (including NPCECs) toward neural cells. This effect is achieved through increasing multiple transcription factors including Pax6, Chx10, Six3, and Cash1. Although IGF-I, EGF, and FGF2 each stimulate this process alone, the combination of IGF-I with either EGF or FGF2 acts synergistically to produce neural cells.81 Therefore, intravitreal administration of growth factors combinations might result in maximum neuroregeneration.
Proliferative Cells Isolated from the Adult Human Peripheral Retina only Transiently Upregulate Key Retinal Markers upon Induced Differentiation
Published in Current Eye Research, 2018
Erik O. Johnsen, Rebecca C. Frøen, Ole Kristoffer Olstad, Bjørn Nicolaissen, Goran Petrovski, Morten C. Moe, Agate Noer
Since an increased expression of early key transcription factors and mature retinal markers was found at Day 7, microarray analysis was performed to identify the global expression changes induced by the differentiation at this time-point. Principle component analysis (PCA) revealed a similar trend in the three different donors tested and indicated a clear clustering of the control and differentiated samples (Figure 4A). Out of the 25 644 transcripts present on the Affymetrix chip, 5060 were significantly (p < 0.05) regulated, with 2814 being upregulated and 2246 being downregulated upon differentiation. Setting a threshold at FC>2, reduced the number of significantly upregulated and downregulated transcripts to 338 and 203, respectively. The heatmap/cluster analyses of the regulated transcripts (FC>2; p < 0.05) also revealed a highly similar expression pattern in the different donor samples with clearly distinct clustering of the differentiated samples from the controls (Figure 4B). The regulated transcripts (FC>2; p < 0.05) were then uploaded into the IPA software and out of the 541 transcripts analyzed, 231 were annotated in the Ingenuity ontology. The IPKB was further used to associate regulated genes with cellular/biological functions and diseases (Supplementary Table S1). The most prominent molecular and cellular functions included cellular growth and proliferation, development, death and survival, and cellular function and maintenance. Physiological system development and function included organismal development, tissue morphology, embryonic development and organ development. The most prominent disease in the analysis was cancer. Out of the 231 transcripts, 23 have been previously implicated in eye development and function, and include growth factors, transmembrane receptors, enzymes, and transcription factors (Table 1). These have been shown to be involved in early eye development (OTX2, HES1, ALDH1A1), retinal development and function (OTX2, PAX6, SIX3, PLXNA4, NTRK2, ALDH1A, BMP4, HES1, FOS), lens development (PAX6, NRCAM, MAF), anterior segment development and function (FOXC2, CHRNA3, SOX4, CYB1B1), cornea epithelial development/structure (ITGB4), choroidal and inner retinal vasculature development (SEMA6A, ICAM1), control of eye growth (EGR1), conjunctival and periorbital development (SNAI2), as well as RPE function (MERTK) and protection against oxidative damage (CP, SOD2).