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Publications (55)
The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mut...
The retina is an exquisitely patterned tissue, with neuronal somata positioned at regular intervals to completely sample the visual field. Cholinergic amacrine cells are spectacular exemplars of precision, distributing in two radial layers and tangentially, forming regular mosaics. Here, we investigated how the intracellular phosphatase Pten and th...
Asymmetric neuronal expansion is thought to drive evolutionary transitions between lissencephalic and gyrencephalic cerebral cortices. We report that Neurog2 and Ascl1 proneural genes together sustain neurogenic continuity and lissencephaly in rodent cortices. Using transgenic reporter mice and human cerebral organoids, we found that Neurog2 and As...
Retinal damage triggers reactive gliosis in Muller glia across vertebrate species, but only in regenerative animals, such as teleost fish, do Muller glia initiate repair; proliferating and undergoing neurogenesis to replace lost cells. By mining scRNA-seq and bulk RNA-seq datasets, we found that Plagl1, a maternally imprinted gene, is dynamically r...
Transition from smooth, lissencephalic brains to highly-folded, gyrencephalic structures is associated with neuronal expansion and breaks in neurogenic symmetry. Here we show that Neurog2 and Ascl1 proneural genes regulate cortical progenitor cell differentiation through cross-repressive interactions to sustain neurogenic continuity in a lissenceph...
Müller glia are specialized retinal cells with stem cell properties in fish and frogs but not in mammals. Current efforts to develop gene therapies to activate mammalian Müller glia for retinal repair will require safe and effective delivery strategies for recombinant adeno-associated viruses (AAVs), vectors of choice for clinical translation. Intr...
Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic’s function in the brain. We show that nuclear Cic expression is strongest in astrocytes and neurons but weaker in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we de...
Zebrin II/aldolase C expression in the normal cerebellum is restricted to a Purkinje cell subset and is the canonical marker for stripes and zones. This spatial restriction has been confirmed in over 30 species of mammals, birds, fish, etc. In a transgenic mouse model in which the Neurogenin 2 gene has been disrupted (Neurog2−/− ), the cerebellum i...
The Plag gene family has three members; Plagl1/Zac1, which is a tumor suppressor gene, and Plag1 and Plagl2, which are proto-oncogenes. All three genes are known to be expressed in embryonic neural progenitors, and Zac1 regulates proliferation, neuronal differentiation and migration in the developing neocortex. Here we examined the functions of Pla...
Neural progenitors undergo temporal identity transitions to sequentially generate the neuronal and glial cells that make up the mature brain. Proneural genes have well characterized roles in promoting neural cell differentiation and subtype specification, but they also regulate the timing of identity transitions through poorly understood mechanisms...
Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic's function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more we...
Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more weak...
PTEN hamartoma tumour syndrome (PHTS) is a heterogeneous group of rare, autosomal dominant disorders associated with PTEN germline mutations. PHTS patients routinely develop hamartomas, which are benign tissue overgrowths comprised of disorganized ‘normal’ cells. Efforts to generate PHTS animal models have been largely unsuccessful due to the early...
A derepression mode of cell-fate specification involving the transcriptional repressors Tbr1, Fezf2, Satb2, and Ctip2 operates in neocortical projection neurons to specify six layer identities in sequence. Less well understood is how laminar fate transitions are regulated in cortical progenitors. The proneural genes Neurog2 and Ascl1 cooperate in p...
Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix loop helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1/Dlx2 and Brn3b homeobox ge...
Capicua (Cic) is an evolutionarily conserved HMG box-containing transcriptional repressor. Mutations in the CIC gene (encoded on human chr 19q) have been found in a diverse range of human cancers, but are most striking in their association with oligodendrogliomas (ODGs), where tumor cells bear resemblance to immature oligodendrocytes or OPCs. CIC m...
Embryonal tumor with multilayered rosettes (ETMR) is an aggressive primitive neuroectodermal brain tumor that affects infants and children under the age of four. Histologically, the tumor is characterized by a growth pattern that includes sheets of primitive cells punctuated by zones of neuropil and multilayered rosettes that are reminiscent of emb...
Unlabelled:
All tissues are genetically programmed to acquire an optimal size that is defined by total cell number and individual cellular dimensions. The retina contains stereotyped proportions of one glial and six neuronal cell types that are generated in overlapping waves. How multipotent retinal progenitors know when to switch from making one...
We report successful retinal cone enrichment and transplantation using a novel cone-GFP reporter mouse line. Using the putative cone photoreceptor-enriched transcript Coiled-Coil Domain Containing 136 (Ccdc136) GFP-trapped allele, we monitored developmental reporter expression, facilitated the enrichment of cones, and evaluated transplanted GFP-lab...
Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated impr...
Molecular characterization of glioblastoma multiforme (gbm) has shown adult gbms to comprise a number of subtypes based on
their gene expression signatures. While these subtypes are somewhat associated with distinct genetic alterations, the relative
contributions of oncogenic driver, cell of origin and developmental stage are not fully understood....
Cancer metastasis is the most critical determinant of overall survival in cancer patients. With the significant advancement in next-generation sequencing technologies, our understanding of mechanism of cancer metastasis has been considerably changed especially after the discovery of noncoding RNAs (ncRNAs). The ncRNAs play critical roles in a varie...
Neural cell fate specification is well understood in the embryonic cerebral cortex, where the proneural genes Neurog2 and Ascl1 are key cell fate determinants. What is less well understood is how cellular diversity is generated in brain tumors. Gliomas and glioneuronal tumors, which are often localized in the cerebrum, are both characterized by a n...
The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons...
The retina is comprised of one glial and six neuronal populations that are generated from a multipotent pool of retinal progenitor cells (RPCs) during development. To give rise to these different cell types, RPCs undergo temporal identity transitions, displaying distinct gene expression profiles at different stages of differentiation. Little, howev...
Progenitor cells undergo a series of stable identity transitions on their way to becoming fully differentiated cells with
unique identities. Each cellular transition requires that new sets of genes are expressed, while alternative genetic programs
are concurrently repressed. Here, we investigated how the proneural gene Neurog2 simultaneously activa...
The neocortex is comprised of six neuronal layers that are generated in a defined temporal sequence. While extrinsic and intrinsic cues are known to regulate the sequential production of neocortical neurons, how these factors interact and function in a coordinated manner is poorly understood. The proneural gene Neurog2 is expressed in progenitors t...
Background:
The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neu...
Photopic ERG oscillatory potential responses in Pten cKO animals. (A–F) Photopic ERG representative trace (A; wild-type is black; Pten cKO is red) and representative OP scalograms (B,C) at the flash intensity of 2.86 cd*s/m2. (D–F) Graphical representation of OP amplitude (D), frequency (E) and latency (F) across 11 steps (−1.63 to 2.86 cd*s/m2).
(...
Ectopic RGC and amacrine cells in Pten cKO retinae. (A–D) Brn3a (A,B) and Pax6 (C,D) immunostaining of P7 retinal cross-sections in wild-type (A,C) and Pten cKO (B,D) retinas. Blue is DAPI counterstain. gcl, ganglion cell layer; inl, inner nuclear layer; ipl, inner plexiform layer; onl, outer nuclear layer; opl, outer plexiform layer. Scale bars =...
Apoptosis is unaltered in Pten cKO retinae. (A–L) Active caspase-3 immunostaining at E15.5 (A–D′), P0 (E–H′) and P7 (I–L′) in wild-type (A–B′,E–F′,I–J′) and Pten cKO (C–D′,G–H′,K–L′) retinas. Blue is DAPI counterstain. gcl, ganglion cell layer; inl, inner nuclear layer; le, lens; onbl, outer neuroblast layer; onl, outer nuclear layer; re, retina. S...
Scotopic, photopic and double-flash ERG analysis of A-waves and B-waves in adult Pten cKO mice. (A–H) Scotopic A-wave amplitudes (A) and implicit times (B) in wild-type and Pten cKO mice. Scotopic B-wave amplitudes (C) and implicit times (D) in wild-type and Pten cKO mice. Photopic B-wave amplitudes (E) and implicit times (F) in wild-type and Pten...
Analysis of electroretinogram responses in adult wild-type and Pten cKO mice.
(DOC)
Analysis of optokinetic contrast sensitivity responses in adult wild-type and Pten cKO mice.
(DOC)
Comparison of retinal cell sizes in wild-type and Pten cKO retinae.
(DOC)
Analysis of horizontal and amacrine cell spacing and wholemount cell counts in P21 wild-type and Pten cKO retinal flatmounts.
(DOC)
The ability to manipulate gene expression is the cornerstone of modern day experimental embryology, leading to the elucidation of multiple developmental pathways. Several powerful and well established transgenic technologies are available to manipulate gene expression levels in mouse, allowing for the generation of both loss- and gain-of-function m...
The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify Zac1, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the...
Figure S1. Expression of Tbr1 and GAD1 in medial cerebellar nuclei in Zac1 mutants. (A,B) Expression of Tbr1 in E18.5 wild-type (A) and Zac1+m/- (B) deep cerebellar nuclei. (C,D) Expression of GAD1 in E18.5 wild-type (C) and Zac1+m/- (D) deep cerebellar nuclei. Med, Medial cerebellar nuclei.
Cajal-Retzius cells are essential pioneer neurons that guide neuronal migration in the developing neocortex. During development, Cajal-Retzius cells arise from distinct progenitor domains that line the margins of the dorsal telencephalon, or pallium. Here, we show that the proneural gene Ascl1 is expressed in Cajal-Retzius cell progenitors in the p...
Endomorphin-1 (EM1, Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (EM2, Tyr-Pro-Phe-Phe-NH2) are natural tetrapeptide ligands of µ-opioid receptors involved in the modulation and attenuation of pain. For a detailed examination of their receptor-binding properties and their metabolic stability, tritium-labelled EM1 and EM2 radioisotopomers were synthesized...
