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Dive into the research topics where Albert E. Ayoub is active.

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Featured researches published by Albert E. Ayoub.


The Journal of Neuroscience | 2006

Molecular and morphological heterogeneity of neural precursors in the mouse neocortical proliferative zones.

Jonathan S. Gal; Yury M. Morozov; Albert E. Ayoub; Mitali Chatterjee; Pasko Rakic; Tarik F. Haydar

The proliferative ventricular zone (VZ) is the main source of projection neurons for the overlying cerebral neocortex. The number and diversity of neocortical neurons is determined, in part, by factors controlling the proliferation and specification of VZ cells during embryonic development. We used a variety of methods, including in utero electroporation with specific cellular markers, computer-assisted serial EM cell reconstruction, and time-lapse multiphoton imaging to characterize the molecular and morphological characteristics of the VZ constituents and to capture their behavior during cell division. Our analyses reveal at least two types of dividing cells in the VZ: (1) radial glial cells (RGCs) that span the entire neocortical wall and maintain contact both at the ventricular and pial surfaces throughout mitotic division, and (2) short neural precursors (SNPs) that possess a ventricular endfoot and a basal process of variable length that is retracted during mitotic division. These two precursor cell classes are present concomitantly in the VZ, but their relative number changes over the course of cortical neurogenesis. Moreover, the SNPs are morphologically, ultrastructurally and molecularly distinct from dividing RGCs. For example, SNPs are marked by their preferential expression of the tubulin α-1 promoter whereas RGCs instead express the glutamate–aspartate transporter and brain lipid binding protein promoters. In contrast to recent studies that suggest that RGCs are the sole type of VZ precursor, the present study indicates that the VZ in murine dorsal telencephalon is similar to that in human and nonhuman primates, because it contains multiple types of neuronal precursors.


Proceedings of the National Academy of Sciences of the United States of America | 2008

Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling

Joshua J. Breunig; Matthew R. Sarkisian; Jon I. Arellano; Yury M. Morozov; Albert E. Ayoub; Sonal Sojitra; Baolin Wang; Richard A. Flavell; Pasko Rakic; Terrence Town

Primary cilia are present on mammalian neurons and glia, but their function is largely unknown. We generated conditional homozygous mutant mice for a gene we termed Stumpy. Mutants lack cilia and have conspicuous abnormalities in postnatally developing brain regions, including a hypoplasic hippocampus characterized by a primary deficiency in neural stem cells known as astrocyte-like neural precursors (ALNPs). Previous studies suggested that primary cilia mediate sonic hedgehog (Shh) signaling. Here, we find that loss of ALNP cilia leads to abrogated Shh activity, increased cell cycle exit, and morphological abnormalities in ALNPs. Processing of Gli3, a mediator of Shh signaling, is also altered in the absence of cilia. Further, key mediators of the Shh pathway localize to ALNP cilia. Thus, selective targeting of Shh machinery to primary cilia confers to ALNPs the ability to differentially respond to Shh mitogenic signals compared to neighboring cells. Our data suggest these organelles are cellular “antennae” critically required to modulate ALNP behavior.


Trends in Neurosciences | 2009

Decision by division: making cortical maps

Pasko Rakic; Albert E. Ayoub; Joshua J. Breunig; Martin H. Dominguez

In the past three decades, mounting evidence has revealed that specification of the basic cortical neuronal classes starts at the time of their final mitotic divisions in the embryonic proliferative zones. This early cell determination continues during the migration of the newborn neurons across the widening cerebral wall, and it is in the cortical plate that they attain their final positions and establish species-specific cytoarchitectonic areas. Here, the development and evolutionary expansion of the neocortex is viewed in the context of the radial unit and protomap hypotheses. A broad spectrum of findings gave insight into the pathogenesis of cortical malformations and the biological bases for the evolution of the modern human neocortex. We examine the history and evidence behind the concept of early specification of neurons and provide the latest compendium of genes and signaling molecules involved in neuronal fate determination and specification.


Cell | 2013

The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb

Justin Cotney; Jing Leng; Jun Yin; Steven K. Reilly; Laura E. DeMare; Deena Emera; Albert E. Ayoub; Pasko Rakic; James P. Noonan

The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human-specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis-regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencing

Albert E. Ayoub; Sunghee Oh; Yanhua Xie; Jing Leng; Justin Cotney; Martin H. Dominguez; James P. Noonan; Pasko Rakic

Characterizing the genetic programs that specify development and evolution of the cerebral cortex is a central challenge in neuroscience. Stem cells in the transient embryonic ventricular and subventricular zones generate neurons that migrate across the intermediate zone to the overlying cortical plate, where they differentiate and form the neocortex. It is clear that not one but a multitude of molecular pathways are necessary to progress through each cellular milestone, yet the underlying transcriptional programs remain unknown. Here, we apply differential transcriptome analysis on microscopically isolated cell populations, to define five transcriptional programs that represent each transient embryonic zone and the progression between these zones. The five transcriptional programs contain largely uncharacterized genes in addition to transcripts necessary for stem cell maintenance, neurogenesis, migration, and differentiation. Additionally, we found intergenic transcriptionally active regions that possibly encode unique zone-specific transcripts. Finally, we present a high-resolution transcriptome map of transient zones in the embryonic mouse forebrain.


Cerebral Cortex | 2013

POU-III Transcription Factors (Brn1, Brn2, and Oct6) Influence Neurogenesis, Molecular Identity, and Migratory Destination of Upper-Layer Cells of the Cerebral Cortex

Martin H. Dominguez; Albert E. Ayoub; Pasko Rakic

The upper layers (II-IV) are the most prominent distinguishing feature of mammalian neocortex compared with avian or reptilian dorsal cortex, and are vastly expanded in primates. Although the time-dependent embryonic generation of upper-layer cells is genetically instructed within their parental progenitors, mechanisms governing cell-intrinsic fate transitions remain obscure. POU-homeodomain transcription factors Pou3f3 and Pou3f2 (Brn1 and Brn2) are known to label postmitotic upper-layer cells, and are redundantly required for their production. We find that the onset of Pou3f3/2 expression actually occurs in ventricular zone (VZ) progenitors, and that Pou3f3/2 subsequently label neural progeny switching from deep-layer Ctip2(+) identity to Satb2(+) upper-layer fate as they migrate to proper superficial positions. By using an Engrailed dominant-negative repressor, we show that sustained neurogenesis after the deep- to upper-layer transition requires the proneual action of Pou3fs in VZ progenitors. Conversely, single-gene overexpression of any Pou3f in early neural progenitors is sufficient to specify the precocious birth of Satb2(+) daughter neurons that extend axons to the contralateral hemisphere, as well as exhibit robust pia-directed migration that is characteristic of upper-layer cells. Finally, we demonstrate that Pou3fs influence multiple stages of neurogenesis by suppressing Notch effector Hes5, and promoting the expression of proneural transcription factors Tbr2 and Tbr1.


Science | 2015

Evolutionary changes in promoter and enhancer activity during human corticogenesis

Steven K. Reilly; Jun Yin; Albert E. Ayoub; Deena Emera; Jing Leng; Justin Cotney; Richard Sarro; Pasko Rakic; James P. Noonan

Of mice, men, and macaque brains The human brain represents a unique evolutionary trajectory. To better understand how the human brain came to be, Reilly et al. sought to identify changes in gene expression between mice, macaques, and humans. They compared epigenetic marks in the embryonic cortex, which revealed changes in gene regulation in biological pathways associated with cortical development. Science, this issue p. 1155 Epigenetic marks associated with evolution of the human cortex gained activity relative to those in mice and monkeys. Human higher cognition is attributed to the evolutionary expansion and elaboration of the human cerebral cortex. However, the genetic mechanisms contributing to these developmental changes are poorly understood. We used comparative epigenetic profiling of human, rhesus macaque, and mouse corticogenesis to identify promoters and enhancers that have gained activity in humans. These gains are significantly enriched in modules of coexpressed genes in the cortex that function in neuronal proliferation, migration, and cortical-map organization. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting that they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes during corticogenesis, providing insight into human cortical evolution.


Proceedings of the National Academy of Sciences of the United States of America | 2008

The stumpy gene is required for mammalian ciliogenesis

Terrence Town; Joshua J. Breunig; Matthew R. Sarkisian; Charalampos G. Spilianakis; Albert E. Ayoub; Xiuxin Liu; Anthony F. Ferrandino; A. Rachel Gallagher; Ming O. Li; Pasko Rakic; Richard A. Flavell

Cilia are present on nearly all cell types in mammals and perform remarkably diverse functions. However, the mechanisms underlying ciliogenesis are unclear. Here, we cloned a previously uncharacterized highly conserved gene, stumpy, located on mouse chromosome 7. Stumpy was ubiquitously expressed, and conditional loss in mouse resulted in complete penetrance of perinatal hydrocephalus (HC) and severe polycystic kidney disease (PKD). We found that cilia in stumpy mutant brain and kidney cells were absent or markedly deformed, resulting in defective flow of cerebrospinal fluid. Stumpy colocalized with ciliary basal bodies, physically interacted with γ-tubulin, and was present along ciliary axonemes, suggesting that stumpy plays a role in ciliary axoneme extension. Therefore, stumpy is essential for ciliogenesis and may be involved in the pathogenesis of human congenital malformations such as HC and PKD.


Nature Neuroscience | 2011

Timing of neurogenesis is a determinant of olfactory circuitry

Fumiaki Imamura; Albert E. Ayoub; Pasko Rakic; Charles A. Greer

An odorant receptor map in mammals that is constructed by the glomerular coalescence of sensory neuron axons in the olfactory bulb is essential for proper odor information processing. How this map is linked with olfactory cortex is unknown. Using a battery of methods, including various markers of cell division in combination with tracers of neuronal connections and time-lapse live imaging, we found that early- and late-generated mouse mitral cells became differentially distributed in the dorsal and ventral subdivisions of the odorant receptor map. In addition, the late-generated mitral cells extended substantially stronger projections to the olfactory tubercle than did the early-generated cells. Together, these data indicate that the odorant receptor map is developmentally linked to the olfactory cortices in part by the birthdate of mitral cells. Thus, different olfactory cortical regions become involved in processing information from distinct regions of the odorant receptor map.


Cell Reports | 2014

Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche.

Nevena V. Radonjić; Albert E. Ayoub; Fani Memi; Xiaojing Yu; Asif Maroof; Igor Jakovcevski; Stewart A. Anderson; Pasko Rakic; Nada Zecevic

Summary Evolutionary elaboration of tissues starts with changes in the genome and location of the stem cells. For example, GABAergic interneurons of the mammalian neocortex are generated in the ventral telencephalon and migrate tangentially to the neocortex, in contrast to the projection neurons originating in the ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon. In human and nonhuman primates, evidence suggests that an additional subset of neocortical GABAergic interneurons is generated in the cortical VZ and a proliferative niche, the outer SVZ. The origin, magnitude, and significance of this species-specific difference are not known. We use a battery of assays applicable to the human, monkey, and mouse organotypic cultures and supravital tissue to identify neuronal progenitors in the cortical VZ/SVZ niche that produce a subset of GABAergic interneurons. Our findings suggest that these progenitors constitute an evolutionary novelty contributing to the elaboration of higher cognitive functions in primates.

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Joshua J. Breunig

Cedars-Sinai Medical Center

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