Jane E Johnson

University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Publications (13)123.95 Total impact

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    ABSTRACT: eLife digest Neurons that arise in the adult nervous system originate from neural stem cells and neural progenitor cells. Neural stem cells have long lives, much of which they spend in a quiescent state. Neural stem cells can also give rise to neural progenitor cells, which proliferate rapidly during their short lives and then ‘differentiate’ into neurons or glia. Unlike some other tissues, it has not been possible to identify or purify neural stem cells directly from the tissue. Consequently, neural stem and progenitor cells have usually been studied retrospectively, based on their ability to form colonies in laboratory cell cultures. A region of the brain called the subventricular zone contains both neural stem cells and neural progenitor cells, and is one of only two regions of the brain where neural stem cells are found in adult mammals. When cells from the subventricular zone are cultured in a way that allows the cells to freely float around (rather than growing on a surface), a few percent form spherical colonies called neurospheres. Since neurosphere-forming cells can self-renew and differentiate into neurons and glia, the ability of cells to form neurospheres has generally been taken as evidence that they are stem cells. However, the exact relationship between neural stem cells and neurosphere-forming cells has been uncertain. Now, Mich, Signer et al. have used a technique called flow cytometry to identify and isolate neural stem cells and neurosphere-forming cells directly from the subventricular zone. The neural stem cells, which Mich, Signer et al. term pre-GEPCOT cells (based on an acronym of the markers used to isolate the cells), were long-lived and quiescent, but they lacked the ability to form colonies in culture. The neurosphere-forming cells, named GEPCOT cells, were short-lived and highly proliferative in the brain. These results demonstrate that the cells that form neurospheres in culture are not stem cells at all, and that real stem cells are not able to form colonies under existing culture conditions. The identification of undifferentiated pre-GEPCOT and GEPCOT cells will make it possible to directly study the properties of these cells inside the mouse brain, and to isolate live cells to test how they function. The results also highlight the need for new tests to study neural stem cell function, given that current tests using neurospheres do not detect stem cells as commonly assumed. DOI: http://dx.doi.org/10.7554/eLife.02669.002
    eLife Sciences 05/2014; 3:e02669. DOI:10.7554/eLife.02669 · 8.52 Impact Factor
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    ABSTRACT: Spinal commissural axons represent a model system for deciphering the molecular logic that regulates the guidance of midline-crossing axons in the developing central nervous system (CNS). Whether the same or specific sets of guidance signals control the navigation of molecularly distinct subtypes of these axons remains an open and largely unexplored question. Although it is well established that post-crossing commissural axons alter their responsiveness to midline-associated guidance cues, our understanding of the repulsive mechanisms that drive the post-crossing segments of these axons away from the midline and whether the underlying guidance systems operate in a commissural axon subtype-specific manner, remains fragmentary at best. Here, we utilize axonally targeted transgenic reporter mice to visualize genetically distinct dorsal interneuron (dI)1 and dI4 commissural axons and show that the repulsive class 3 semaphorin (Sema3) guidance receptor Neuropilin 2 (Npn2), is selectively expressed on the dI1 population and is required for the guidance of post-crossing dI1, but not dI4, axons. Consistent with these observations, the midline-associated Npn2 ligands, Sema3F and Sema3B, promote the collapse of dI1, but not dI4, axon-associated growth cones in vitro. We also identify, for the first time, a discrete GABAergic population of ventral commissural neurons/axons in the embryonic mouse spinal cord that expresses Npn2, and show that Npn2 is required for the proper guidance of their post-crossing axons. Together, our findings indicate that Npn2 is selectively expressed in distinct populations of commissural neurons in both the dorsal and ventral spinal cord, and suggest that Sema3-Npn2 signaling regulates the guidance of post-crossing commissural axons in a population-specific manner.
    Neural Development 07/2013; 8(1):15. DOI:10.1186/1749-8104-8-15 · 3.37 Impact Factor
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    ABSTRACT: The lineage-specific basic-helix-loop-helix transcription factor Ptf1a is a critical driver for development of both the pancreas and nervous system. How one transcription factor controls diverse programs of gene expression is a fundamental question in developmental biology. To uncover molecular strategies for the program-specific functions of Ptf1a, we identified bound genomic regions in vivo during development of both tissues. Most regions bound by Ptf1a are specific to each tissue, lie near genes needed for proper formation of each tissue, and coincide with regions of open chromatin. The specificity of Ptf1a binding is encoded in the DNA surrounding the Ptf1a-bound sites, because these regions are sufficient to direct tissue-restricted reporter expression in transgenic mice. Fox and Sox factors were identified as potential lineage-specific modifiers of Ptf1a binding, since binding motifs for these factors are enriched in Ptf1a-bound regions in pancreas and neural tube, respectively. Of the Fox factors expressed during pancreatic development, Foxa2 plays a major role. Indeed, Ptf1a and Foxa2 co-localize in embryonic pancreatic chromatin and can act synergistically in cell transfection assays. Together, these findings indicate that lineage-specific chromatin landscapes likely constrain the DNA-binding of Ptf1a, and identify Fox and Sox gene families as part of this process.
    Molecular and Cellular Biology 06/2013; DOI:10.1128/MCB.00364-13 · 5.04 Impact Factor
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    ABSTRACT: Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.
    Proceedings of the National Academy of Sciences 07/2012; 109(31):12592-7. DOI:10.1073/pnas.1204710109 · 9.81 Impact Factor
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    ABSTRACT: Neural progenitor cells within the developing thalamus are spatially organized into distinct populations. Their correct specification is critical for generating appropriate neuronal subtypes in specific locations during development. Secreted signaling molecules, such as sonic hedgehog (Shh) and Wnts, are required for the initial formation of the thalamic primordium. Once thalamic identity is established and neurogenesis is initiated, Shh regulates the positional identity of thalamic progenitor cells. Although Wnt/β-catenin signaling also has differential activity within the thalamus during this stage of development, its significance has not been directly addressed. In this study, we used conditional gene manipulations in mice and explored the roles of β-catenin signaling in the regional identity of thalamic progenitor cells. We found β-catenin is required during thalamic neurogenesis to maintain thalamic fate while suppressing prethalamic fate, demonstrating that regulation of regional fate continues to require extrinsic signals. These roles of β-catenin appeared to be mediated at least partly by regulating two basic helix-loop-helix (bHLH) transcription factors, Neurog1 and Neurog2. β-Catenin and Shh signaling function in parallel to specify two progenitor domains within the thalamus, where individual transcription factors expressed in each progenitor domain were regulated differently by the two signaling pathways. We conclude that β-catenin has multiple functions during thalamic neurogenesis and that both Shh and β-catenin pathways are important for specifying distinct types of thalamic progenitor cells, ensuring that the appropriate neuronal subtypes are generated in the correct locations.
    Development 06/2012; 139(15):2692-702. DOI:10.1242/dev.072314 · 6.27 Impact Factor
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    ABSTRACT: Distinct classes of neurons are generated from progenitor cells distributed in characteristic dorsoventral patterns in the developing spinal neural tube. We define restricted neural progenitor populations by the discrete, nonoverlapping expression of Ngn1, Math1, and Mash1. Crossinhibition between these bHLH factors is demonstrated and provides a mechanism for the generation of discrete bHLH expression domains. This precise control of bHLH factor expression is essential for proper neural development since as demonstrated in both loss- and gain-of-function experiments, expression of Math1 or Ngn1 in dorsal progenitor cells determines whether LH2A/B- or dorsal Lim1/2-expressing interneurons will develop. Together, the data suggest that although Math1 and Ngn1 appear to be redundant with respect to neurogenesis, they have distinct functions in specifying neuronal subtype in the dorsal neural tube.
    Neuron 09/2001; 31(2):219-32. DOI:10.1016/S0896-6273(01)00367-1 · 15.98 Impact Factor
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    ABSTRACT: Compared to neurons, the intracellular mechanisms that control glial differentiation are still poorly understood. We show here that oligodendrocyte lineage cells express the helix-loop-helix proteins Mash1 and Id2. Although Mash1 has been found to regulate neuronal development, we found that in the absence of Mash1 oligodendrocyte differentiation occurs normally. In contrast, we found that overexpression of Id2 powerfully inhibits oligodendrocyte differentiation, that Id2 normally translocates out of the nucleus at the onset of differentiation, and that absence of Id2 induces premature oligodendrocyte differentiation in vitro. These findings demonstrate that Id2 is a component of the intracellular mechanism that times oligodendrocyte differentiation and point to the existence of an as yet unidentified MyoD-like bHLH protein necessary for oligodendrocyte differentiation.
    Neuron 04/2001; 29(3):603-14. DOI:10.1016/S0896-6273(01)00237-9 · 15.98 Impact Factor
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    ABSTRACT: The basic helix-loop-helix transcription factor Neurogenin2 (NGN2) is expressed in distinct populations of neural progenitor cells within the developing central and peripheral nervous systems. Transgenic mice containing ngn2/lacZ reporter constructs were used to study the regulation of ngn2 in the developing spinal cord. ngn2/lacZ transgenic embryos containing sequence found 5' or 3' to the ngn2 coding region express lacZ in domains that reflect the spatial and temporal expression profile of endogenous ngn2. A 4.4-kb fragment 5' of ngn2 was sufficient to drive lacZ expression in the ventral neural tube, whereas a 1.0-kb fragment located 3' of ngn2 directed expression to both dorsal and ventral domains. Persistent -gal activity revealed that the NGN2 progenitor cells in the dorsal domain give rise to a subset of interneurons that send their axons to the floor plate, and the NGN2 progenitors in the ventral domain give rise to a subset of motor neurons. We identified a discrete element that is required for the activity of the ngn2 enhancer specifically in the ventral neural tube. Thus, separable regulatory elements that direct ngn2 expression to distinct neural progenitor populations have been defined.
    Developmental Biology 02/2001; 229(2):327-39. DOI:10.1006/dbio.2000.9984 · 3.64 Impact Factor
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    Andrea Meredith, Jane E. Johnson
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    ABSTRACT: Mash1, a neural-specific bHLH transcription factor, is essential for the formation of multiple CNS and PNS neural lineages. Transcription from the Mash1 locus is elevated in mice null for Mash1, suggesting that MASH1 normally acts to repress its own transcription. This activity is contrary to the positive autoregulation of other proneural bHLH proteins. To investigate the mechanisms involved in this process, sequences flanking the Mash1 gene were tested for the ability to mediate negative autoregulation. A Mash1/lacZ transgene containing 36 kb of cis-regulatory sequence exhibits an increase in lacZ expression in the Mash1 mutant background, which phenocopies the observation of transcriptional autoregulation at the endogenous Mash1 locus. Using Mash1/lacZ lines with progressively less cis-acting sequence, autoregulatory responsive elements were demonstrated to colocalize with a previously characterized 1.2-kb CNS enhancer. Mutations of E-box sites within this enhancer did not result in an apparent loss of autoregulation, suggesting that MASH1 does not directly repress its own transcription. Interestingly, these mutations did not indicate any underlying positive auto- or cross-regulation of Mash1. Furthermore, the loss of autoregulation in the Mash1 mutant background is reminiscent of a loss of lateral inhibitory signaling. However, mutations in HES consensus sites, the likely purveyors of Notch-mediated lateral inhibition, do not support a role for these sites in negative autoregulation. We hypothesize that MASH1 normally inhibits its own expression indirectly, possibly through a HES-mediated repression of positive regulators or through novel HES binding sites.
    Developmental Biology 07/2000; 222(2-222):336-346. DOI:10.1006/dbio.2000.9697 · 3.64 Impact Factor
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    ABSTRACT: Mash1, a transcription factor of the basic helix-loop-helix class, is expressed during embryogenesis in restricted regions of the nervous system. An essential role for Mash1 in neural development was demonstrated previously in mice carrying a targeted disruption of the Mash1 gene. Regulation of the precise temporal and spatial expression of Mash1 is thus likely to be important for proper neural development. In this study, sequences that regulate Mash1 expression in the central nervous system were characterized by assaying the expression of lacZ reporter genes in transgenic embryos. A 1158-bp enhancer localized approximately 7 kb upstream of the Mash1 coding region was identified. Deletions within this enhancer region reveal the presence of both positive and negative cis-acting elements. Analysis of multiple sequences within the enhancer demonstrate that different elements preferentially function in different regions within the Mash1-specific CNS expression domain. In addition, a role for sequences 3' of the Mash1 coding region is revealed, providing evidence for posttranscriptional control of Mash1 expression in multiple CNS domains.
    Developmental Biology 06/1998; 197(1):106-16. DOI:10.1006/dbio.1998.8873 · 3.64 Impact Factor
  • Sunita Verma-Kurvari, Jane E Johnson
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    ABSTRACT: Proteins of the achaete-scute family of transcription factors play important roles in neurogenesis in both invertebrates and vertebrates. Here, we report the cloning and characterization of a Japanese pufferfish, Fugu rubripes achaete-scute homolog 1, Fash1. Sequence alignment of the predicted amino acid sequence of Fash1 with other vertebrate homologs of the achaete scute homolog 1 subclass shows that the carboxyl 2/3 of the protein, including the basic helix-loop-helix, a putative nuclear localization signal and several consensus phosphorylation sites, is highly conserved. Strikingly, the similarity in this region between eight vertebrate species is close to 90%.
    Gene 11/1997; 200(1-2):145-8. DOI:10.1016/S0378-1119(97)00394-6 · 2.08 Impact Factor
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    ABSTRACT: Interactions between cells help to elaborate pattern within the vertebrate central nervous system (CNS)
    Nature 10/1997; 389(6654):966-970. DOI:10.1038/40146 · 42.35 Impact Factor
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    ABSTRACT: Mash1 is a transcription factor required during embryogenesis for the development of multiple neural lineages. It is expressed in restricted domains at specific stages in the developing central and peripheral nervous systems and in the developing olfactory epithelium. We have investigated the regulation of Mash1 expression during embryogenesis using transgenic mice containing Mash1/lacZ reporter constructs. Cis-acting regulatory elements controlling Mash1 expression in the central nervous system are located within an 8-kb sequence upstream of the Mash1 coding region. This 8-kb sequence does not contain elements directing expression to the peripheral nervous system, olfactory epithelium, or retina. Sequences outside this 8 kb but within 36 kb of the Mash1 locus contain elements responsible for expression in the autonomic division of the peripheral nervous system. However, transgene expression in embryos containing the 36-kb sequence was never detected in the olfactory epithelium and retina. Thus, regulatory elements driving expression in these lineages may be at even greater distances from the Mash1 coding region. These data provide evidence for complex regulation of Mash1 expression in which multiple lineage-specific cis-acting regulatory regions span greater than 36 kb of the Mash1 locus. Further characterization of these regions will facilitate the study of factors that regulate the temporal and spatial expression of Mash1 during development. In addition, the regulatory sequences identified here can direct expression of heterologous genes to developing neural lineages that normally express Mash1, thus providing an important tool for examining the function of candidate regulatory genes in mammalian nervous system development.
    Developmental Biology 01/1997; 180(2):605-17. DOI:10.1006/dbio.1996.0332 · 3.64 Impact Factor