I’ve had a longstanding interest in the signaling events that drive organogenesis and tissue homeostasis. In mammals, the neurosensory cells of the inner ear that detect sound, gravity and acceleration have extremely low regenerative capacity, making the developmental processes that control their number, location, and function incredibly important. As a graduate student this lead me to study how inner ear progenitor cells are specified in response to Hedgehog and Wnt signaling pathways. Both the Hedgehog and Wnt cell signaling pathways are used iteratively during development to pattern many tissues and damage to either pathway frequently results in birth defects or cancer. Since the same signals are used repeated for different outcomes in a context dependent manner, my postdoctoral studies initially focused on determining how Hedgehog target genes are selected in a developmental system, the postnatal proliferation of cerebellar granule neuron progenitor cells. Later in my postdoc my research interests shifted and I focused on the function of the Hedgehog target gene Missing-in-Metastasis (Mtss1) in coupling the cell membrane and cytoskeleton on neurons. Mtss1 can function as a docking site for regulatory kinases and phosphatases to control the local actin cytoskeleton and regulate the localization of membrane proteins. This process is key for cerebellar Purkinje neuron function and survival and may underlie several distinct neurodegenerative diseases.

Education & Certifications

  • Ph.D., University of Pennsylvania School of Medicine, Cell and Molecular Biology (2012)
  • BA, University of Colorado, Boulder, Biochemistry, MCD Biology (2005)


All Publications

  • MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias. Proceedings of the National Academy of Sciences of the United States of America Brown, A. S., Meera, P., Altindag, B., Chopra, R., Perkins, E. M., Paul, S., Scoles, D. R., Tarapore, E., Magri, J., Huang, H., Jackson, M., Shakkottai, V. G., Otis, T. S., Pulst, S. M., Atwood, S. X., Oro, A. E. 2018


    The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

    View details for PubMedID 30530649

  • Granule neuron precursor cell proliferation is regulated by NFIX and intersectin 1 during postnatal cerebellar development. Brain structure & function Fraser, J., Essebier, A., Brown, A. S., Davila, R. A., Sengar, A. S., Tu, Y., Ensbey, K. S., Day, B. W., Scott, M. P., Gronostajski, R. M., Wainwright, B. J., Boden, M., Harvey, T. J., Piper, M. 2018


    Cerebellar granule neurons are the most numerous neuronal subtype in the central nervous system. Within the developing cerebellum, these neurons are derived from a population of progenitor cells found within the external granule layer of the cerebellar anlage, namely the cerebellar granule neuron precursors (GNPs). The timely proliferation and differentiation of these precursor cells, which, in rodents occurs predominantly in the postnatal period, is tightly controlled to ensure the normal morphogenesis of the cerebellum. Despite this, our understanding of the factors mediating how GNP differentiation is controlled remains limited. Here, we reveal that the transcription factor nuclear factor I X (NFIX) plays an important role in this process. Mice lacking Nfix exhibit reduced numbers of GNPs during early postnatal development, but elevated numbers of these cells at postnatal day 15. Moreover, Nfix-/- GNPs exhibit increased proliferation when cultured in vitro, suggestive of a role for NFIX in promoting GNP differentiation. At a mechanistic level, profiling analyses using both ChIP-seq and RNA-seq identified the actin-associated factor intersectin 1 as a downstream target of NFIX during cerebellar development. In support of this, mice lacking intersectin 1 also displayed delayed GNP differentiation. Collectively, these findings highlight a key role for NFIX and intersectin 1 in the regulation of cerebellar development.

    View details for PubMedID 30511336

  • LAP2 Proteins Chaperone GLI1 Movement between the Lamina and Chromatin to Regulate Transcription. Cell Mirza, A. N., McKellar, S. A., Urman, N. M., Brown, A. S., Hollmig, T., Aasi, S. Z., Oro, A. E. 2018


    Understanding transcription factor navigation through the nucleus remains critical for developing targeted therapeutics. The GLI1 transcription factor must maintain maximal Hedgehog pathway output in basal cell carcinomas (BCCs), and we have previously shown that resistant BCCs increase GLI1 deacetylation through atypical protein kinase Ciota/lambda (aPKC) andHDAC1. Here we identify a lamina-associated polypeptide 2 (LAP2) isoform-dependent nuclear chaperoning system that regulates GLI1 movement between the nuclear lamina and nucleoplasm to achieve maximal activation. LAP2beta forms a two-site interaction with the GLI1 zinc-finger domain and acetylation site, stabilizing an acetylation-dependent reserve on the inner nuclear membrane (INM). By contrast, the nucleoplasmic LAP2alpha competes with LAP2beta for GLI1 while scaffolding HDAC1 to deacetylate the secondary binding site. aPKC functions to promote GLI1 association with LAP2alpha, promoting egress off the INM. GLI1 intranuclear trafficking by LAP2 isoforms represents a powerful signal amplifier in BCCs with implications for zinc finger-based signal transduction and therapeutics.

    View details for PubMedID 30503211

  • Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nature medicine Whitson, R. J., Lee, A., Urman, N. M., Mirza, A., Yao, C. Y., Brown, A. S., Li, J. R., Shankar, G., Fry, M. A., Atwood, S. X., Lee, E. Y., Hollmig, S. T., Aasi, S. Z., Sarin, K. Y., Scott, M. P., Epstein, E. H., Tang, J. Y., Oro, A. E. 2018; 24 (3): 271–81


    Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

    View details for PubMedID 29400712

    View details for PubMedCentralID PMC5839965

  • Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment. JCI insight Mirza, A. N., Fry, M. A., Urman, N. M., Atwood, S. X., Roffey, J., Ott, G. R., Chen, B., Lee, A., Brown, A. S., Aasi, S. Z., Hollmig, T., Ator, M. A., Dorsey, B. D., Ruggeri, B. R., Zificsak, C. A., Sirota, M., Tang, J. Y., Butte, A., Epstein, E., Sarin, K. Y., Oro, A. E. 2017; 2 (21)


    Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Ɩ/ʎ (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.

    View details for PubMedID 29093271

  • The cochlear sensory epithelium derives from Wnt responsive cells in the dorsomedial otic cup DEVELOPMENTAL BIOLOGY Brown, A. S., Rakowiecki, S. M., Li, J. Y., Epstein, D. J. 2015; 399 (1): 177-187


    Wnt1 and Wnt3a secreted from the dorsal neural tube were previously shown to regulate a gene expression program in the dorsal otic vesicle that is necessary for vestibular morphogenesis (Riccomagno et al., 2005. Genes Dev. 19, 1612-1623). Unexpectedly, Wnt1(-/-); Wnt3a(-/-) embryos also displayed a pronounced defect in the outgrowth of the ventrally derived cochlear duct. To determine how Wnt signaling in the dorsal otocyst contributes to cochlear development we performed a series of genetic fate mapping experiments using two independent Wnt responsive driver strains (TopCreER and Gbx2(CreER)) that when crossed to inducible responder lines (Rosa(lacZ) or Rosa(zsGreen)) permanently labeled dorsomedial otic progenitors and their derivatives. Tamoxifen time course experiments revealed that most vestibular structures showed some degree of labeling when recombination was induced between E7.75 and E12.5, consistent with continuous Wnt signaling activity in this tissue. Remarkably, a population of Wnt responsive cells in the dorsal otocyst was also found to contribute to the sensory epithelium of the cochlear duct, including auditory hair and support cells. Similar results were observed with both TopCreER and Gbx2(CreER) strains. The ventral displacement of Wnt responsive cells followed a spatiotemporal sequence that initiated in the anterior otic cup at, or immediately prior to, the 17-somite stage (E9) and then spread progressively to the posterior pole of the otic vesicle by the 25-somite stage (E9.5). These lineage-tracing experiments identify the earliest known origin of auditory sensory progenitors within a population of Wnt responsive cells in the dorsomedial otic cup.

    View details for DOI 10.1016/j.ydbio.2015.01.001

    View details for Web of Science ID 000350709300016

    View details for PubMedID 25592224

  • Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development DEVELOPMENT Brown, A. S., Epstein, D. J. 2011; 138 (18): 3967-3976


    In mouse embryos lacking sonic hedgehog (Shh), dorsoventral polarity within the otic vesicle is disrupted. Consequently, ventral otic derivatives, including the cochlear duct and saccule, fail to form, and dorsal otic derivatives, including the semicircular canals, endolymphatic duct and utricle, are malformed or absent. Since inner ear patterning and morphogenesis are heavily dependent on extracellular signals derived from tissues that are also compromised by the loss of Shh, the extent to which Shh signaling acts directly on the inner ear for its development is unclear. To address this question, we generated embryos in which smoothened (Smo), an essential transducer of Hedgehog (Hh) signaling, was conditionally inactivated in the otic epithelium (Smo(ecko)). Ventral otic derivatives failed to form in Smo(ecko) embryos, whereas vestibular structures developed properly. Consistent with these findings, we demonstrate that ventral, but not dorsal, otic identity is directly dependent on Hh. The role of Hh in cochlear-vestibular ganglion (cvg) formation is more complex, as both direct and indirect signaling mechanisms are implicated. Our data suggest that the loss of cvg neurons in Shh(-/-) animals is due, in part, to an increase in Wnt responsiveness in the otic vesicle, resulting in the ectopic expression of Tbx1 in the neurogenic domain and subsequent repression of Ngn1 transcription. A mitogenic role for Shh in cvg progenitor proliferation was also revealed in our analysis of Smo(ecko) embryos. Taken together, these data contribute to a better understanding of the intrinsic and extrinsic signaling properties of Shh during inner ear development.

    View details for DOI 10.1242/dev.066126

    View details for Web of Science ID 000294156000013

    View details for PubMedID 21831920