Professional Education


  • Doctor of Philosophy, University of North Carolina, Chapel Hill (2013)
  • Bachelor of Science, Lenoir-Rhyne College (2006)

Stanford Advisors


All Publications


  • TBR1 regulates autism risk genes in the developing neocortex. Genome research Notwell, J. H., Heavner, W. E., Darbandi, S. F., Katzman, S., McKenna, W. L., Ortiz-Londono, C. F., Tastad, D., Eckler, M. J., Rubenstein, J. L., McConnell, S. K., Chen, B., Bejerano, G. 2016; 26 (8): 1013-1022

    Abstract

    Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.

    View details for DOI 10.1101/gr.203612.115

    View details for PubMedID 27325115

  • Compensatory Actions of Ldb Adaptor Proteins During Corticospinal Motor Neuron Differentiation. Cerebral cortex (New York, N.Y. : 1991) Leone, D. P., Panagiotakos, G., Heavner, W. E., Joshi, P., Zhao, Y., Westphal, H., McConnell, S. K. 2016

    Abstract

    Although many genes that specify neocortical projection neuron subtypes have been identified, the downstream effectors that control differentiation of those subtypes remain largely unknown. Here, we demonstrate that the LIM domain-binding proteins Ldb1 and Ldb2 exhibit dynamic and inversely correlated expression patterns during cerebral cortical development. Ldb1-deficient brains display severe defects in proliferation and changes in regionalization, phenotypes resembling those of Lhx mutants. Ldb2-deficient brains, on the other hand, exhibit striking phenotypes affecting layer 5 pyramidal neurons: Immature neurons have an impaired capacity to segregate into mature callosal and subcerebral projection neurons. The analysis of Ldb2 single-mutant mice reveals a compensatory role of Ldb1 for Ldb2 during corticospinal motor neuron (CSMN) differentiation. Animals lacking both Ldb1 and Ldb2 uncover the requirement for Ldb2 during CSMN differentiation, manifested as incomplete CSMN differentiation, and ultimately leading to a failure of the corticospinal tract.

    View details for DOI 10.1093/cercor/bhw003

    View details for PubMedID 26830346

  • Satb2 Regulates the Differentiation of Both Callosal and Subcerebral Projection Neurons in the Developing Cerebral Cortex CEREBRAL CORTEX Leone, D. P., Heavner, W. E., Ferenczi, E. A., Dobreva, G., Huguenard, J. R., Grosschedl, R., McConnell, S. K. 2015; 25 (10): 3406-3419

    Abstract

    The chromatin-remodeling protein Satb2 plays a role in the generation of distinct subtypes of neocortical pyramidal neurons. Previous studies have shown that Satb2 is required for normal development of callosal projection neurons (CPNs), which fail to extend axons callosally in the absence of Satb2 and instead project subcortically. Here we conditionally delete Satb2 from the developing neocortex and find that neurons in the upper layers adopt some electrophysiological properties characteristic of deep layer neurons, but projections from the superficial layers do not contribute to the aberrant subcortical projections seen in Satb2 mutants. Instead, axons from deep layer CPNs descend subcortically in the absence of Satb2. These data demonstrate distinct developmental roles of Satb2 in regulating the fates of upper and deep layer neurons. Unexpectedly, Satb2 mutant brains also display changes in gene expression by subcerebral projection neurons (SCPNs), accompanied by a failure of corticospinal tract (CST) formation. Altering the timing of Satb2 ablation reveals that SCPNs require an early expression of Satb2 for differentiation and extension of the CST, suggesting that early transient expression of Satb2 in these cells plays an essential role in development. Collectively these data show that Satb2 is required by both CPNs and SCPNs for proper differentiation and axon pathfinding.

    View details for DOI 10.1093/cercor/bhu156

    View details for Web of Science ID 000366454000012

    View details for PubMedID 25037921

  • A family of transposable elements co-opted into developmental enhancers in the mouse neocortex NATURE COMMUNICATIONS Notwell, J. H., Chung, T., Heavner, W., Bejerano, G. 2015; 6

    View details for DOI 10.1038/ncomms7644

    View details for Web of Science ID 000353040900001

  • Establishment of the neurogenic boundary of the mouse retina requires cooperation of SOX2 and WNT signaling NEURAL DEVELOPMENT Heavner, W. E., Andoniadou, C. L., Pevny, L. H. 2014; 9

    Abstract

    Eye development in vertebrates relies on the critical regulation of SOX2 expression. Humans with mutations in SOX2 often suffer from eye defects including anophthalmia (no eye) and microphthalmia (small eye). In mice, deletion of Sox2 in optic cup progenitor cells results in loss of neural competence and cell fate conversion of the neural retina to a non-neurogenic fate, specifically the acquisition of fate associated with progenitors of the ciliary epithelium. This fate is also promoted with constitutive expression of stabilized β-Catenin in the optic cup, where the WNT pathway is up-regulated. We addressed whether SOX2 co-ordinates the neurogenic boundary of the retina through modulating the WNT/β-Catenin pathway by using a genetic approach in the mouse.Upon deletion of Sox2 in the optic cup, response to WNT signaling was expanded, correlating with loss of neural competence, cell fate conversion of the neural retina to ciliary epithelium primordium and, in addition, increased cell cycle time of optic cup progenitors. Removal of Ctnnb1 rescued the cell fate conversion; however, the loss of neural competence and the proliferation defect resulting from lack of SOX2 were not overcome. Lastly, central Sox2-deficient optic cup progenitor cells exhibited WNT-independent up-regulation of D-type Cyclins.We propose two distinct roles for SOX2 in the developing retina. Our findings suggest that SOX2 antagonizes the WNT pathway to maintain a neurogenic fate and, in contrast, regulates cycling of optic cup progenitors in a WNT-independent manner. Given that WNT signaling acting upstream of SOX2 has been implicated in the tumorigenicity of embryonic stem cell-derived retinal progenitor cells, our results distinguish the endogenous role of WNT signaling in early optic cup patterning and support a WNT-independent role for SOX2 in maintaining retinal progenitor cell proliferation.

    View details for DOI 10.1186/1749-8104-9-27

    View details for Web of Science ID 000346939000001

    View details for PubMedID 25488119

  • Eye development and retinogenesis. Cold Spring Harbor perspectives in biology Heavner, W., Pevny, L. 2012; 4 (12)

    Abstract

    Three embryonic tissue sources-the neural ectoderm, the surface ectoderm, and the periocular mesenchyme-contribute to the formation of the mammalian eye. For this reason, the developing eye has presented an invaluable system for studying the interactions among cells and, more recently, genes, in specifying cell fate. This article describes how the eye primordium is specified in the anterior neural plate by four eye field transcription factors and how the optic vesicle becomes regionalized into three distinct tissue types. Specific attention is given to how cross talk between the optic vesicle and surface ectoderm contributes to lens and optic cup formation. This article also describes how signaling networks and cell movements set up axes in the optic cup and establish the multiple cell fates important for vision. How multipotent retinal progenitor cells give rise to the six neuronal and one glial cell type in the mature retina is also explained. Finally, the history and progress of cellular therapeutics for the treatment of degenerative eye disease is outlined. Throughout this article, special attention is given to how disruption of gene function causes ocular malformation in humans. Indeed, the accessibility of the eye has contributed much to our understanding of the basic processes involved in mammalian development.

    View details for DOI 10.1101/cshperspect.a008391

    View details for PubMedID 23071378

  • Combinatorial regulation of optic cup progenitor cell fate by SOX2 and PAX6. Development (Cambridge, England) Matsushima, D., Heavner, W., Pevny, L. H. 2011; 138 (3): 443-54

    Abstract

    In humans, haploinsufficiency of either SOX2 or PAX6 is associated with microphthalmia, anophthalmia or aniridia. In this study, through the genetic spatiotemporal specific ablation of SOX2 on both wild-type and Pax6-haploinsufficent backgrounds in the mouse, we have uncovered a transcriptionally distinct and developmentally transient stage of eye development. We show that genetic ablation of SOX2 in the optic cup results in complete loss of neural competence and eventual cell fate conversion to non-neurogenic ciliary epithelium. This cell fate conversion is associated with a striking increase in PAX6, and genetically ablating SOX2 on a Pax6-haploinsufficient background partially rescues the Sox2-mutant phenotype. Collectively, these results demonstrate that precise regulation of the ratio of SOX2 to PAX6 is necessary to ensure accurate progenitor cell specification, and place SOX2 as a decisive factor of neural competence in the retina.

    View details for DOI 10.1242/dev.055178

    View details for PubMedID 21205789