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Wittmann, Walter
Publications (4 of 4) Show all publications
Panaliappan, T. K., Wittmann, W., Jidigam, V. K., Mercurio, S., Bertolini, J. A., Sghari, S., . . . Gunhaga, L. (2018). Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation. Development, 145(2), Article ID dev153791.
Open this publication in new window or tab >>Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation
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2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 2, article id dev153791Article in journal (Refereed) Published
Abstract [en]

The transcription factor Sox2 is necessary to maintain pluripotency of embryonic stem cells, and to regulate neural development. Neurogenesis in the vertebrate olfactory epithelium persists from embryonic stages through adulthood. The role Sox2 plays for the development of the olfactory epithelium and neurogenesis within has, however, not been determined. Here, by analysing Sox2 conditional knockout mouse embryos and chick embryos deprived of Sox2 in the olfactory epithelium using CRISPR-Cas9, we show that Sox2 activity is crucial for the induction of the neural progenitor gene Hes5 and for subsequent differentiation of the neuronal lineage. Our results also suggest that Sox2 activity promotes the neurogenic domain in the nasal epithelium by restricting Bmp4 expression. The Sox2-deficient olfactory epithelium displays diminished cell cycle progression and proliferation, a dramatic increase in apoptosis and finally olfactory pit atrophy. Moreover, chromatin immunoprecipitation data show that Sox2 directly binds to the Hes5 promoter in both the PNS and CNS. Taken together, our results indicate that Sox2 is essential to establish, maintain and expand the neuronal progenitor pool by suppressing Bmp4 and upregulating Hes5 expression.

Place, publisher, year, edition, pages
Company of Biologists Ltd, 2018
Keywords
Sox2, Hes5, Olfactory epithelium, Neurogenesis, Mouse
National Category
Developmental Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-145166 (URN)10.1242/dev.153791 (DOI)000424412000009 ()2-s2.0-85041301091 (Scopus ID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2023-03-24Bibliographically approved
Wittmann, W., Iulianella, A. & Gunhaga, L. (2014). Cux2 acts as a critical regulator for neurogenesis in the olfactory epithelium of vertebrates. Developmental Biology, 388(1), 35-47
Open this publication in new window or tab >>Cux2 acts as a critical regulator for neurogenesis in the olfactory epithelium of vertebrates
2014 (English)In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 388, no 1, p. 35-47Article in journal (Refereed) Published
Abstract [en]

Signaling pathways and transcription factors are crucial regulators of vertebrate neurogenesis, exerting their function in a spatial and temporal manner. Despite recent advances in our understanding of the molecular regulation of embryonic neurogenesis, little is known regarding how different signaling pathways interact to tightly regulate this process during the development of neuroepithelia. To address this, we have investigated the events lying upstream and downstream of a key neurogenic factor, the Cut-like homeodomain transcription factor-2 (Cux2), during embryonic neurogenesis in chick and mouse. By using the olfactory epithelium as a model for neurogenesis we have analyzed mouse embryos deficient in Cux2, as well as chick embryos exposed to Cux2 silencing (si) RNA or a Cux2 over-expression construct. We provide evidence that enhanced BMP activity increases Cux2 expression and suppresses olfactory neurogenesis in the chick olfactory epithelium. In addition, our results show that up-regulation of Cux2, either BMP-induced or ectopically over-expressed, reduce Delta1 expression and suppress proliferation. Interestingly, the loss of Cux2 activity, using mutant mice or siRNA in chick, also diminishes neurogenesis, Notch activity and cell proliferation in the olfactory epithelium. Our results suggest that controlled low levels of Cux2 activity are necessary for proper Notch signaling, maintenance of the proliferative pool and ongoing neurogenesis in the olfactory epithelium. Thus, we demonstrate a novel conserved mechanism in vertebrates in which levels of Cux2 activity play an important role for ongoing neurogenesis in the olfactory epithelium. (C) 2014 The Authors. Published by Elsevier Inc.

Keywords
Cux2, Neurogenesis, BMP, Notch, Olfactory, Development, Chick, Mouse
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-88274 (URN)10.1016/j.ydbio.2014.01.026 (DOI)000333378200004 ()24512687 (PubMedID)2-s2.0-84895425095 (Scopus ID)
Available from: 2014-05-05 Created: 2014-04-29 Last updated: 2023-03-24Bibliographically approved
Wittmann, W., Schimmang, T. & Gunhaga, L. (2014). Progressive effects of N-myc deficiency on proliferation, neurogenesis, and morphogenesis in the olfactory epithelium. Developmental Neurobiology, 74(6), 643-656
Open this publication in new window or tab >>Progressive effects of N-myc deficiency on proliferation, neurogenesis, and morphogenesis in the olfactory epithelium
2014 (English)In: Developmental Neurobiology, ISSN 1932-8451, E-ISSN 1932-846X, Vol. 74, no 6, p. 643-656Article in journal (Refereed) Published
Abstract [en]

N-myc belongs to the myc proto-oncogene family, which is involved in numerous cellular processes such as proliferation, growth, apoptosis, and differentiation. Conditional deletion of N-myc in the mouse nervous system disrupted brain development, indicating that N-myc plays an essential role during neural development. How the development of the olfactory epithelium and neurogenesis within are affected by the loss of N-myc has, however, not been determined. To address these issues, we examined an N-myc(Foxg1Cre) conditional mouse line, in which N-myc is depleted in the olfactory epithelium. First changes in N-myc mutants were detected at E11.5, with reduced proliferation and neurogenesis in a slightly smaller olfactory epithelium. The phenotype was more pronounced at E13.5, with a complete lack of Hes5-positive progenitor cells, decreased proliferation, and neurogenesis. In addition, stereological analyses revealed reduced cell size of post-mitotic neurons in the olfactory epithelium, which contributed to a smaller olfactory pit. Furthermore, we observed diminished proliferation and neurogenesis also in the vomeronasal organ, which likewise was reduced in size. In addition, the generation of gonadotropin-releasing hormone neurons was severely reduced in N-myc mutants. Thus, diminished neurogenesis and proliferation in combination with smaller neurons might explain the morphological defects in the N-myc depleted olfactory structures. Moreover, our results suggest an important role for N-myc in regulating ongoing neurogenesis, in part by maintaining the Hes5-positive progenitor pool. In summary, our results provide evidence that N-myc deficiency in the olfactory epithelium progressively diminishes proliferation and neurogenesis with negative consequences at structural and cellular levels. 

Keywords
vomeronasal organ, mouse, neurogenesis, olfactory epithelium, N-myc
National Category
Neurology Developmental Biology
Identifiers
urn:nbn:se:umu:diva-89452 (URN)10.1002/dneu.22162 (DOI)000335362300007 ()2-s2.0-84899905537 (Scopus ID)
Available from: 2014-07-03 Created: 2014-06-03 Last updated: 2023-03-24Bibliographically approved
Wittmann, W. & McLennan, I. S. (2013). The bed nucleus of the stria terminalis has developmental and adult forms in mice, with the male bias in the developmental form being dependent on testicular AMH. Hormones and Behavior, 64(4), 605-610
Open this publication in new window or tab >>The bed nucleus of the stria terminalis has developmental and adult forms in mice, with the male bias in the developmental form being dependent on testicular AMH
2013 (English)In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 64, no 4, p. 605-610Article in journal (Refereed) Published
Abstract [en]

Canonically, the sexual dimorphism in the brain develops perinatally, with adult sexuality emerging due to the activating effects of pubescent sexual hormones. This concept does not readily explain why children have a gender identity and exhibit sex-stereotypic behaviours. These phenomena could be explained if some aspects of the sexual brain networks have childhood forms, which are transformed at puberty to generate adult sexuality. The bed nucleus of stria terminalis (BNST) is a dimorphic nucleus that is sex-reversed in transsexuals but not homosexuals. We report here that the principal nucleus of the BNST (BNSTp) of mice has developmental and adult forms that are differentially regulated. In 20-day-old prepubescent mice, the male bias in the principal nucleus of the BNST (BNSTp) was moderate (360 +/- 6 vs 288 +/- 12 calbindin(+ve) neurons, p < 0.0001), and absent in mice that lacked a gonadal hormone, AMH. After 20 days, the number of BNSTp neurons increased in the male mice by 25% (p < 0.0001) and decreased in female mice by 15% (p = 0.0012), independent of AMH. Adult male AMH-deficient mice had a normal preference for sniffing female pheromones (soiled bedding), but exhibited a relative disinterest in both male and female pheromones. This suggests that male mice require AMH to undergo normal social development. The reported observations provide a rationale for examining AMH levels in children with gender identity disorders and disorders of socialization that involve a male bias.

Keywords
Sexual dimorphism, Testes, Testosterone, Gender, Bed nucleus of the stria terminalis, Calbindin
National Category
Behavioral Sciences Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-84134 (URN)10.1016/j.yhbeh.2013.08.017 (DOI)000326849600005 ()2-s2.0-84884914382 (Scopus ID)
Available from: 2013-12-17 Created: 2013-12-16 Last updated: 2023-03-24Bibliographically approved
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