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1.
Am J Hum Genet ; 95(3): 326-31, 2014 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-25192046

RESUMEN

Gonadotropin-releasing hormone (GnRH) neurons originate outside the CNS in the olfactory placode and migrate into the CNS, where they become integral components of the hypothalamic-pituitary-gonadal (HPG) axis. Disruption of this migration results in Kallmann syndrome (KS), which is characterized by anosmia and pubertal failure due to hypogonadotropic hypogonadism. Using candidate-gene screening, autozygosity mapping, and whole-exome sequencing in a cohort of 30 individuals with KS, we searched for genes newly associated with KS. We identified homozygous loss-of-function mutations in FEZF1 in two independent consanguineous families each with two affected siblings. The FEZF1 product is known to enable axons of olfactory receptor neurons (ORNs) to penetrate the CNS basal lamina in mice. Because a subset of axons in these tracks is the migratory pathway for GnRH neurons, in FEZF1 deficiency, GnRH neurons also fail to enter the brain. These results indicate that FEZF1 is required for establishment of the central component of the HPG axis in humans.


Asunto(s)
Proteínas de Unión al ADN/genética , Síndrome de Kallmann/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Adolescente , Adulto , Animales , Axones/metabolismo , Axones/patología , Encéfalo/metabolismo , Encéfalo/patología , Niño , Familia , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Hipogonadismo , Sistema Hipotálamo-Hipofisario , Masculino , Ratones , Neuronas Receptoras Olfatorias/metabolismo , Neuronas Receptoras Olfatorias/patología , Linaje , Estudios Prospectivos , Proteínas Represoras , Adulto Joven
2.
Endocrinology ; 157(5): 1956-66, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27014940

RESUMEN

The first mutation in a gene associated with a neuronal migration disorder was identified in patients with Kallmann Syndrome, characterized by hypogonadotropic hypogonadism and anosmia. This pathophysiological association results from a defect in the development of the GnRH and the olfactory system. A recent genetic screening of Kallmann Syndrome patients revealed a novel mutation in CCDC141. Little is known about CCDC141, which encodes a coiled-coil domain containing protein. Here, we show that Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration. Our findings in human patients and mouse models predict that CCDC141 takes part in embryonic migration of GnRH neurons enabling them to form a hypothalamic neuronal network to initiate pulsatile GnRH secretion and reproductive function.


Asunto(s)
Movimiento Celular/genética , Hormona Liberadora de Gonadotropina/metabolismo , Síndrome de Kallmann/genética , Mutación , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Animales , Humanos , Ratones , Proteínas del Tejido Nervioso/fisiología , Neuronas/citología
3.
J Exp Med ; 212(3): 287-95, 2015 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-25732305

RESUMEN

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.


Asunto(s)
Enfermedad de Alzheimer/patología , Macrófagos/metabolismo , Macrófagos/patología , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Factores de Edad , Anciano , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Antígenos Comunes de Leucocito/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Ratones Transgénicos , Receptores Inmunológicos/genética , Regulación hacia Arriba , Proteínas tau/metabolismo
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