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Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
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The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
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The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
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The cadherins are a superfamily of cell adhesion molecules comprising over 180 variants, with specific tissues expressing a particular combination of cadherin types. Cadherins generally exhibit homophilic binding; i.e., cadherins on one cell bind to cadherins of the same or closely related type on another cell. Thus, cells of the same type have a specific affinity to bind to each other and sort themselves into clusters to form tissues.
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During embryogenesis, cells become progressively committed to different fates through a two-step process: specification followed by determination. Specification is demonstrated by removing a segment of an early embryo, “neutrally” culturing the tissue in vitro—for example, in a petri dish with simple medium—and then observing the derivatives. If the cultured region gives rise to cell types that it would normally generate in the embryo, this means that it is specified. In...
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The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
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El control de la señalización WNT por KDM5C durante el desarrollo afecta la cognición

Violetta Karwacki-Neisius1, Ahram Jang2,3, Engin Cukuroglu4

  • 1Division of Newborn Medicine and Epigenetics Program, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. violetta.karwacki-neisius@childrens.harvard.edu.

Nature
|February 21, 2024
PubMed
Resumen

Las mutaciones del gen KDM5C causan discapacidad intelectual al interrumpir el tiempo de desarrollo neurológico. Restaurar la señalización WNT temporalmente durante el desarrollo puede corregir los cambios celulares y rescatar los déficits cognitivos.

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Área de la Ciencia:

  • La neurociencia
  • La genética
  • Biología del desarrollo

Sus antecedentes:

  • Las mutaciones KDM5C son comunes en la discapacidad intelectual ligada al X, pero los mecanismos subyacentes no están claros.
  • Comprender el papel de KDM5C es crucial para abordar las deficiencias cognitivas.

Objetivo del estudio:

  • Aclarar la función de KDM5C en el desarrollo neurológico y su relación con la discapacidad intelectual.
  • Investigar los mecanismos moleculares por los cuales las mutaciones KDM5C conducen al deterioro cognitivo.

Principales métodos:

  • Se utilizaron células madre pluripotentes inducidas derivadas de pacientes humanos y modelos de ratón knockout Kdm5c.
  • Se realizaron análisis celulares, transcriptómicos, de cromatina y de comportamiento.
  • Investigó el papel de la modulación de la vía de señalización WNT.

Principales resultados:

  • Identificó KDM5C como un regulador crítico del tiempo de desarrollo neurológico.
  • Demostró el control directo de KDM5C sobre la salida de WNT durante una ventana de desarrollo específica.
  • Se demostró que la modulación transitoria de la vía WNT puede rescatar los déficits celulares y conductuales asociados con la interrupción de KDM5C.

Conclusiones:

  • KDM5C actúa como una salvaguarda para el desarrollo neurológico adecuado, y su interrupción causa discapacidad intelectual.
  • La modulación de señalización WNT transitoria ofrece una estrategia terapéutica potencial para la discapacidad intelectual asociada con KDM5C.
  • Reveló la naturaleza transitorio de la señalización WNT en la influencia de las funciones cognitivas de larga duración como la memoria y la ansiedad.