The Genetics of Primary Microcephaly Jayaraman, Divya; Bae, Byoung-Il; Walsh, Christopher A
Annual review of genomics and human genetics,
08/2018, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Primary microcephaly (MCPH, for "microcephaly primary hereditary") is a disorder of brain development that results in a head circumference more than 3 standard deviations below the mean for age and ...gender. It has a wide variety of causes, including toxic exposures, in utero infections, and metabolic conditions. While the genetic microcephaly syndromes are relatively rare, studying these syndromes can reveal molecular mechanisms that are critical in the regulation of neural progenitor cells, brain size, and human brain evolution. Many of the causative genes for MCPH encode centrosomal proteins involved in centriole biogenesis. However, other MCPH genes fall under different mechanistic categories, notably DNA replication and repair. Recent gene discoveries and functional studies have implicated novel cellular processes, such as cytokinesis, centromere and kinetochore function, transmembrane or intracellular transport, Wnt signaling, and autophagy, as well as the apical polarity complex. Thus, MCPH genes implicate a wide variety of molecular and cellular mechanisms in the regulation of cerebral cortical size during development.
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci ...with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations—identified by whole-genome and targeted “HAR-ome” sequencing—showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior.
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•Human accelerated regions exhibit regulatory activity during neural development•De novo CNVs impacting HARs are enriched in individuals with ASD•Biallelic HAR mutations underlie up to 5% of consanguineous ASD cases•Regulatory mutations reveal novel genetic architecture of ASD
Mutations in genomic loci that have undergone accelerated evolution in humans are associated with increased risk for autism.
Genetic Changes Shaping the Human Brain Bae, Byoung-Il; Jayaraman, Divya; Walsh, Christopher A.
Developmental cell,
02/2015, Letnik:
32, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The development and function of our brain are governed by a genetic blueprint, which reflects dynamic changes over the history of evolution. Recent progress in genetics and genomics, facilitated by ...next-generation sequencing and single-cell sorting, has identified numerous genomic loci that are associated with a neuroanatomical or neurobehavioral phenotype. Here, we review some of the genetic changes in both protein-coding and noncoding regions that affect brain development and evolution, as well as recent progress in brain transcriptomics. Understanding these genetic changes may provide novel insights into neurological and neuropsychiatric disorders, such as autism and schizophrenia.
Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD ...repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.
•Wdr62 and Aspm interact genetically to control brain size in mice•Loss of Wdr62 or Aspm causes centriole duplication defects proportional to microcephaly•WDR62 and ASPM are maternal centriolar proteins that recruit CPAP to the centrosome•Loss of Wdr62 and Aspm causes gene dose-dependent disruption of the apical complex
Jayaraman et al. show that microcephaly proteins Wdr62 and Aspm localize to the maternal centriole and physically interact. Mice lacking Wdr62, Aspm, or both show gene dose-dependent defects in brain size, centriole duplication, centrosomal localization of CPAP, and the apical complex, which plays a critical role in cell fate.
The human neocortex has numerous specialized functional areas whose formation is poorly understood. Here, we describe a 15–base pair deletion mutation in a regulatory element of GPR56 that ...selectively disrupts human cortex surrounding the Sylvian fissure bilaterally including "Broca's area," the primary language area, by disrupting regional GPR56 expression and blocking RFX transcription factor binding. GPR56 encodes a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor required for normal cortical development and is expressed in cortical progenitor cells. GPR56 expression levels regulate progenitor proliferation. GPR56 splice forms are highly variable between mice and humans, and the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression. Our data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution.
GPR56, a member of the adhesion G protein-coupled receptor family, is abundantly expressed in cells of the developing cerebral cortex, including neural progenitor cells and developing neurons. The ...human GPR56 gene has multiple presumptive promoters that drive the expression of the GPR56 protein in distinct patterns. Similar to coding mutations of the human GPR56 gene that may cause GPR56 dysfunction, a 15-bp homozygous deletion in the cis-regulatory element upstream of the noncoding exon 1 of GPR56 (e1m) leads to the cerebral cortex malformation and epilepsy. To clarify the expression profile of the e1m promoter-driven GPR56 in primate brain, we generated a transgenic marmoset line in which EGFP is expressed under the control of the human minimal e1m promoter. In contrast to the endogenous GPR56 protein, which is highly enriched in the ventricular zone of the cerebral cortex, EGFP is mostly expressed in developing neurons in the transgenic fetal brain. Furthermore, EGFP is predominantly expressed in GABAergic neurons, whereas the total GPR56 protein is evenly expressed in both GABAergic and glutamatergic neurons, suggesting the GABAergic neuron-preferential activity of the minimal e1m promoter. These results indicate a possible pathogenic role for GABAergic neuron in the cerebral cortex of patients with GPR56 mutations.
Despite recent advances in molecularly targeted therapies and immunotherapies, the effective treatment of advanced-stage cancers remains a largely unmet clinical need. Identifying driver mechanisms ...of cancer aggressiveness can lay the groundwork for the development of breakthrough therapeutic strategies. Assembly factor for spindle microtubules (ASPM) was initially identified as a centrosomal protein that regulates neurogenesis and brain size. Mounting evidence has demonstrated the pleiotropic roles of ASPM in mitosis, cell cycle progression, and DNA double-strand breaks (DSB) repair. Recently, the exon-18-preserved isoform 1 of ASPM has emerged as a critical regulator of cancer stemness and aggressiveness in various malignant tumor types. Here, we describe the domain compositions of ASPM and its transcript variants and overview their expression patterns and prognostic significance in cancers. A summary is provided of recent progress in the molecular elucidation of ASPM as a regulatory hub of development- and stemness-associated signaling pathways, such as the Wnt, Hedgehog, and Notch pathways, and of DNA DSB repair in cancer cells. The review emphasizes the potential utility of ASPM as a cancer-agnostic and pathway-informed prognostic biomarker and therapeutic target.
What Are Mini-Brains? Bae, Byoung-il; Walsh, Christopher A.
Science (American Association for the Advancement of Science),
10/2013, Letnik:
342, Številka:
6155
Journal Article
Recenzirano
The human cerebral cortex defines us as who we are. Its development and function underlie complex human cognitive behavior, while its malfunction or degeneration causes countless neurological and ...psychiatric diseases. It has evolved markedly in humans compared to other animals and, therefore, no animal model truly recapitulates these human-specific features (1). We are currently limited to identifying genetic causes of abnormal brain development and function, observing brain shape and activity through imaging, and examining postmortem brain tissues. You simply cannot analyze human brain development directly. The more we try to model human disease in the mouse-with its miniscule cerebral cortex one-thousandth the size of a human's-the more we recognize the limitations of animal models. Lancaster et al. (2) have provided a major leap by developing a method to grow miniature human brain-like structures (cerebral organoids) from embryonic stem cells in vitro (2). The "minibrains" recapitulate a surprising number of features of human embryonic brain development, heralding a new phase of modeling human disease.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it ...the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits cell death. R-(-)-Deprenyl (deprenyl) ameliorates the progression of disability in early Parkinson's disease and also has neuroprotective actions. We show that deprenyl and a related agent, TCH346, in subnanomolar concentrations, prevent S-nitrosylation of GAPDH, the binding of GAPDH to Siah, and nuclear translocation of GAPDH. In mice treated with the dopamine neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), low doses of deprenyl prevent binding of GAPDH and Siahl in the dopamineenriched corpus striatum.
Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade. Diverse apoptotic stimuli activate inducible nitric oxide synthase (iNOS) or neuronal ...NOS (nNOS), with the generated nitric oxide (NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (Refs 10,11,12,13,14,15), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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