Insulin antibodies retard and insulin accelerates growth and differentiation in early embryos

Pablo, Flora de; Girbau, Matias; Gomez, J. A.; Hernandez, E.; Roth, Jesse

doi:10.2337/diabetes.34.10.1063

Cited by 35 publications

(16 citation statements)

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“…We did not attempt to block insulin synthesis in the embryo in ovo, as the large volume of the egg provides a significant amount of insulin (21). Nonetheless, both the maternally derived egg insulin and the embryonic product of preproinsulin mRNA can be neutralized with antibodies or antisense ODN, disrupting normal development (5,17). High glucose has no effect on apoptosis in neurulating chick embryos.…”

Section: Resultsmentioning

confidence: 99%

“…Altered control of cell death is associated with an increasing number of pathologies, including embryonic abnormalities in the nervous system (2)(3)(4). We previously showed that balanced insulin signaling is required for normal chick development at early embryonic stages, since blockade with anti-insulin antibodies or an excess of insulin was deleterious to the embryo (5,6). In the chick embryo, before the emergence of pancreas, preproinsulin mRNA levels are developmentally regulated but are not increased by high glucose (7).…”

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confidence: 99%

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Unprocessed Proinsulin Promotes Cell Survival During Neurulation in the Chick Embryo

et al. 2002

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We have chosen a vertebrate model accessible during neurulation, the chick, for analysis of endogenous insulin signaling and its contribution to early embryonic cell survival. Unlike rodents, humans and chickens have a single preproinsulin gene, facilitating its prepancreatic expression characterization. We show that in vivo interference with embryonic insulin signaling using antisense oligonucleotides against the insulin receptor increases apoptosis during neurulation. In contrast, high glucose administration does not increase the level of apoptosis in culture or in vivo. Exogenous insulin and, remarkably, proinsulin achieve similar survival protective effects at 10 ؊8 mol/l. The low abundant preproinsulin mRNA from the prepancreatic embryo is translated to a protein that remains as unprocessed proinsulin. This concurs with the absence of prohormone convertase 2 (PC2) in the embryo, whereas PC2 is present later in embryonic pancreas. A C-peptidespecific antibody stains proinsulin-containing neuroepithelial cells of the chick embryo in early neurulation, as well as other cells in mesoderm-and endoderm-derived structures in the 2.5-day embryo. We have determined by 5-RACE (rapid amplification of cDNA ends), and confirmed by RNase protection assay, that prepancreatic and pancreatic proinsulin mRNA differ in their first exon, suggesting differential transcriptional regulation. All these data support the role of endogenous proinsulin in cell survival in the chick embryo during important pathophysiologic periods of early development.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Unprocessed Proinsulin Promotes Cell Survival During Neurulation in the Chick Embryo

et al. 2002

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“…Both blocking anti-insulin antibodies and an excess of insulin are deleterious for growth in the chick embryo [68,71]. In cultured rat embryos, low insulin levels cause retarded growth and development [72].…”

Section: Biological Functions Of Proinsulin/insulin In Early Developmentmentioning

confidence: 99%

Proinsulin in development: new roles for an ancient prohormone

Hernández‐Sánchez¹,

Mansilla²,

Rosa³

et al. 2006

Diabetologia

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In postnatal organisms, insulin is well known as an essential anabolic hormone responsible for maintaining glucose homeostasis. Its biosynthesis by the pancreatic beta cell has been considered a model of tissue-specific gene expression. However, proinsulin mRNA and protein have been found in embryonic stages before the formation of the pancreatic primordium, and later, in extrapancreatic tissues including the nervous system. Phylogenetic studies have also confirmed that production of insulin-like peptides antecedes the morphogenesis of a pancreas, and that these peptides contribute to normal development. In recent years, other roles for insulin distinct from its metabolic function have emerged also in vertebrates. During embryonic development, insulin acts as a survival factor and is involved in early morphogenesis. These findings are consistent with the observation that, at these stages, the proinsulin gene product remains as the precursor form, proinsulin. Independent of its low metabolic activity, proinsulin stimulates proliferation in developing neuroretina, as well as cell survival and cardiogenesis in early embryos. Insulin/proinsulin levels are finely regulated during development, since an excess of the protein interferes with correct morphogenesis and is deleterious for the embryo. This fine-tuned regulation is achieved by the expression of alternative embryonic proinsulin transcripts that have diminished translational activity.

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“…1) from Drosophila (2), chicken (3,4), and mouse (5). In Xenopus laevis large numbers of oocytes and developing embryos are accessible at all stages, making this organism an excellent model for studying the role of growth factors in development (6).…”

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confidence: 99%

Genes encoding receptors for insulin and insulin-like growth factor I are expressed in Xenopus oocytes and embryos.

Scavo

Shuldiner²,

Serrano³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Insulin and insulin-like growth factor I (IGF-I) initiate their metabolic, growth, and differentiation effects through binding to the insulin receptor and the IGF-I receptor, two members of the tyrosine kinase family of receptors. To study the role of these peptides and receptors in early development, we used the polymerase chain reaction and embryo-derived RNA to generate partial cDNA sequences of the insulin receptor and IGF-I receptor from the amphibian Xenopus laevis. Three unique tyrosine kinase-related sequences were obtained. Two of the nucleotide sequences, XTK la and XTK lb, corresponded to peptides that share 92% amino acid identity, and each is 89% identical to the human insulin receptor. The third sequence, XTK 2, corresponds to a peptide that has 92% amino acid identity with the human IGF-I receptor but only 80% identity with XTK la and XTK lb. On the basis of these similarities, the pattern of conserved amino acids, and the tetraploid nature of the Xenopus genome, we suggest that XTK la and XTK lb most likely represent the product of two different nonallelic insulin receptor genes, while XTK2 may be one of the probable two Xenopus IGF-I receptor genes. By reverse transcription-polymerase chain reaction and gene-specific hybridization, expression of the three XTK sequences was detected in the oocyte, unfertilized egg, and embryos through gastrulation, neurulation, and tailbud stages. Competition binding assays with Xenopus membrane preparations demonstrated insulin receptors and IGF-I receptors in older tadpoles. IGF-I receptors were also present in oocytes, eggs, and gastrula embryos. By contrast, insulin binding was present but atypical in oocytes and was barely detected in eggs and gastrula embryos. The expression of receptors for insulin and IGF-I in early Xenopus embryos and their apparent distinct developmental regulation suggest that these molecules and their ligands may be important in early Xenopus development.

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Insulin antibodies retard and insulin accelerates growth and differentiation in early embryos

Cited by 35 publications

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Unprocessed Proinsulin Promotes Cell Survival During Neurulation in the Chick Embryo

Unprocessed Proinsulin Promotes Cell Survival During Neurulation in the Chick Embryo

Proinsulin in development: new roles for an ancient prohormone

Genes encoding receptors for insulin and insulin-like growth factor I are expressed in Xenopus oocytes and embryos.

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