loss-of-function mutations cause microcephaly and short stature.

Cell number is a major determinant of organism size in mammals. In humans, gene mutations in cell cycle components result in restricted growth through reduced cell numbers. Here we identified biallelic mutations in as a cause of microcephaly and short stature.

In silico protein interaction screening uncovers DONSON's role in replication initiation.

CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates.

PRIM1 deficiency causes a distinctive primordial dwarfism syndrome.

DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals.

Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma.

The mechanisms generating cancer-initiating mutations are not well understood. Sonic hedgehog (SHH) pathway activation is frequent in medulloblastoma (MB), with PTCH1 mutations being a common initiating event. Here we investigated the role of the developmental mitogen SHH in initiating carcinogenesis in the cells of origin: granule cell progenitors (GCPs).

Recent advances in SHH medulloblastoma progression: tumor suppressor mechanisms and the tumor microenvironment.

Medulloblastoma, the most common of the malignant pediatric brain tumors, is a group of four molecularly and clinically distinct cancers with different cells of origin. One of these medulloblastoma groups displays activation of Sonic hedgehog (SHH) signaling and originates from granule cell precursors of the developing cerebellum. Ongoing basic and clinical research efforts are tailored to discover targeted and safer therapies, which rely on the identification of the basic mechanisms regulating tumor initiation, progression, and metastasis.

Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression.

Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1 mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1 mice) or the superficial epidermis (Inv-Dsg2/Ptc1 mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively.

Evasion of cell senescence in SHH medulloblastoma.

The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1 mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia.

Evasion of Cell Senescence Leads to Medulloblastoma Progression.

How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1(+/-) mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence.

[Differential effects of attention deficit/hyperactivity disorder subtypes in event-related potentials].

Background: To better understand the neurophysiological substrates in attention deficit/hyperactivity disorder (ADHD), a study was performed on of event-related potentials (ERPs) in Colombian patients with inattentive and combined ADHD.

Methods: A case-control, cross-sectional study was designed. The sample was composed of 180 subjects between 5 and 15 years of age (mean, 9.

The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.

During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown.

[Protocol for the combination of neurohistological techniques on vibratome obtained sections].

Introduction: The histological study of the nervous system requires the use of special techniques. Currently, no methods are available to visualize simultaneously all the cellular constituents of nervous tissue.

Objectives: A protocol was adapted for staining nervous tissue by modification of a formerly difficult procedure.