Home Forebrain development–an intricate balance decides between health and disease
Article
Licensed
Unlicensed Requires Authentication

Forebrain development–an intricate balance decides between health and disease

  • Tamrat Meshka Mamo

    Tamrat Meshka Mamo studied biology at Addis Ababa University in Ethiopia where he obtained his Bachelor and moved on to obtain his MSc in Neuroscience from the Bordeaux Segalen University in France. Tamrat received his PhD in Molecular Medicine from the University of Hannover in Germany. In 2019 he joined the Max Delbrück Center for Molecular Medicine in Berlin as a postdoctoral researcher in the laboratory of Annette Hammes. Tamrat was awarded several scholarships, including the Netherlands research fellowship, the Neurasmus master scholarship and the Hannover Biomedical Research School scholarship. Tamrat is currently working on the identification of novel disease relevant modulators that affect SHH pathway capacity and primary cilia dynamics in the developing brain.

     ORCID logo     and Annette Hammes

    Annette Hammes received her PhD at the Julius-Maximilians University of Würzburg. She is now a group leader at the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association on Berlin, Germany. The work of her team focuses on molecular mechanisms underlying defects in neuronal stem and progenitor cell fate decision during early embryonic development causing congenital defects of the central nervous system.

     ORCID logo EMAIL logo
Published/Copyright: October 24, 2022
Become an author with De Gruyter Brill
Author Information
Neuroforum
From the journal Neuroforum Volume 28 Issue 4

Abstract

Patients carrying pathogenic gene variants encoding factors linked to the sonic hedgehog (SHH) pathway suffer from severe congenital brain malformations including holoprosencephaly (HPE). A poorly understood feature of these common anomalies is the highly variable penetrance, even amongst family members, carrying the same mutation. Modifier genes–genetic variants that can affect the phenotypic outcome of the primary disease-causing gene–contribute to this variability within pedigrees. Modifier genes can confer resilience or susceptibility to a disease, but are difficult to identify in humans. Studying the complex genetic interactions in mouse models of human congenital disorders can be instrumental in the identification of genes, that powerfully modulate SHH signaling pathway capacity and ultimately the penetrance of genetic disturbances. Understanding the underlying complex molecular mechanisms of disease aetiology and can support directing future genetic linkage studies in humans.

Zusammenfassung

Patienten mit pathogenen Genvarianten, die in dem Sonic-Hedgehog (SHH) Signalweg eine Rolle spielen, leiden an schweren angeborenen Fehlbildungen des Gehirns, einschließlich Holoprosenzephalie (HPE). Ein kaum verstandenes Merkmal dieser häufigen Anomalien ist die sehr unterschiedliche Penetranz, selbst unter Familienmitgliedern, die dieselbe Mutation tragen. Modikatorgene – genetische Varianten, die das phänotypische Ergebnis des primären krankheitsverursachenden Gens beeinflussen können – tragen zu dieser Variabilität bei. Modifikatorgene können Resilienz oder Anfälligkeit für eine Erkrankung verleihen; diese Gene sind aber beim Menschen schwer zu identifizieren. Die Untersuchung der komplexen genetischen Interaktionen in Mausmodellen menschlicher angeborener Störungen kann zu der Identifizierung von Genen beitragen, die SHH Signalwegkapazität und letztendlich die Penetranz genetischer Störungen stark modulieren. Das Verständnis der zugrunde liegenden komplexen molekularen Mechanismen der Krankheitsätiologie kann richtungsgebend für zukünftige Studien an den genetischen Ursachen bestimmter kongenitaler Erkrankungen beim Menschen sein.

Keywords: congenital disorder; genetic modifier; holoprosencephaly; primary cilium; sonic hedgehog signaling
Schlüsselwörter: angeborene Erkrankungen; genetische Modifikatoren; Holoprosenzephalie; primäres Zilium; Sonic Hedgehog Signalweg
Corresponding author: Annette Hammes, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany, E-mail:

About the authors

Tamrat Meshka Mamo

Tamrat Meshka Mamo studied biology at Addis Ababa University in Ethiopia where he obtained his Bachelor and moved on to obtain his MSc in Neuroscience from the Bordeaux Segalen University in France. Tamrat received his PhD in Molecular Medicine from the University of Hannover in Germany. In 2019 he joined the Max Delbrück Center for Molecular Medicine in Berlin as a postdoctoral researcher in the laboratory of Annette Hammes. Tamrat was awarded several scholarships, including the Netherlands research fellowship, the Neurasmus master scholarship and the Hannover Biomedical Research School scholarship. Tamrat is currently working on the identification of novel disease relevant modulators that affect SHH pathway capacity and primary cilia dynamics in the developing brain.

Annette Hammes

Annette Hammes received her PhD at the Julius-Maximilians University of Würzburg. She is now a group leader at the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association on Berlin, Germany. The work of her team focuses on molecular mechanisms underlying defects in neuronal stem and progenitor cell fate decision during early embryonic development causing congenital defects of the central nervous system.

Acknowledgements

We would like to thank Dr. Nora Mecklenburg, Dr. Izabela Kowalczyk, Dr. Franziska Witte, Jessica Görne, Alena Laier, Dr. Hannes Gonschior, Dr. Martin Lehmann, Dr. Matthias Richter, Dr. Anje Sporbert, Dr. Bettina Purfürst and Dr. Norbert Hübner as co-authors of the study that we refer to in the last part of this review (Mecklenburg et al., 2021).

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Anderson, R.M., Lawrence, A.R., Stottmann, R.W., Bachiller, D., and Klingensmith, J. (2002). Chordin and noggin promote organizing centers of forebrain development in the mouse. Dev. Camb. Engl. 129, 4975–4987, https://doi.org/10.1242/dev.129.21.4975.Search in Google Scholar PubMed

Baardman, M.E., Zwier, M.V., Wisse, L.J., Groot, A.C.G., Kerstjens-Frederikse, W.S., Hofstra, R.M.W., Jurdzinski, A., Hierck, B.P., Jongbloed, M.R.M., Berger, R.M.F., et al.. (2016). Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development. Dis. Model. Mech. 9, 413–425, https://doi.org/10.1242/dmm.022053.Search in Google Scholar PubMed PubMed Central

Bertrand, N., and Dahmane, N. (2006). Sonic hedgehog signaling in forebrain development and its interactions with pathways that modify its effects. Trends Cell Biol. 16, 597–605, https://doi.org/10.1016/j.tcb.2006.09.007.Search in Google Scholar PubMed

Chiang, C., Litingtung, Y., Lee, E., Young, K.E., Corden, J.L., Westphal, H., and Beachy, P.A. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413, https://doi.org/10.1038/383407a0.Search in Google Scholar PubMed

Christ, A., Christa, A., Kur, E., Lioubinski, O., Bachmann, S., Willnow, T.E., and Hammes, A. (2012). LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Dev. Cell 22, 268–278, https://doi.org/10.1016/j.devcel.2011.11.023.Search in Google Scholar PubMed

Christ, A., Marczenke, M., and Willnow, T.E. (2020). LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation. Hum. Mol. Genet. 29, 3183–3196, https://doi.org/10.1093/hmg/ddaa200.Search in Google Scholar PubMed PubMed Central

Cole, F., and Krauss, R.S. (2003). Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Curr. Biol. CB 13, 411–415, https://doi.org/10.1016/s0960-9822(03)00088-5.Search in Google Scholar PubMed

Fliegauf, M., Benzing, T., and Omran, H. (2007). When cilia go bad: cilia defects and ciliopathies. Nat. Rev. Mol. Cell Biol. 8, 880–893, https://doi.org/10.1038/nrm2278.Search in Google Scholar PubMed

Geng, X., Acosta, S., Lagutin, O., Gil, H.J., and Oliver, G. (2016). Six3 dosage mediates the pathogenesis of holoprosencephaly. Development 143, 4462–4473, https://doi.org/10.1242/dev.132142.Search in Google Scholar PubMed PubMed Central

Geng, X., Speirs, C., Lagutin, O., Inbal, A., Liu, W., Solnica-Krezel, L., Jeong, Y., Epstein, D.J., and Oliver, G. (2008). Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev. Cell 15, 236–247, https://doi.org/10.1016/j.devcel.2008.07.003.Search in Google Scholar PubMed PubMed Central

Geng, X., and Oliver, G. (2009). Pathogenesis of holoprosencephaly. J. Clin. Invest. 119, 1403–1413, https://doi.org/10.1172/JCI38937.Search in Google Scholar PubMed PubMed Central

Gerdes, J.M., Davis, E.E., and Katsanis, N. (2009). The vertebrate primary cilium in development, homeostasis, and disease. Cell 137, 32–45, https://doi.org/10.1016/j.cell.2009.03.023.Search in Google Scholar PubMed PubMed Central

Gigante, E.D. and Caspary, T. (2020). Signaling in the primary cilium through the lens of the Hedgehog pathway. Wiley Interdiscip. Rev. Dev. Biol. 6, e377, https://doi.org/10.1002/wdev.377.Search in Google Scholar PubMed PubMed Central

Goetz, S.C., and Anderson, K.V. (2010). The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331–344, https://doi.org/10.1038/nrg2774.Search in Google Scholar PubMed PubMed Central

Hammes, A., Andreassen, T.K., Spoelgen, R., Raila, J., Hubner, N., Schulz, H., Metzger, J., Schweigert, F.J., Luppa, P.B., Nykjaer, A., et al.. (2005). Role of endocytosis in cellular uptake of sex steroids. Cell 122, 751–762, https://doi.org/10.1016/j.cell.2005.06.032.Search in Google Scholar PubMed

Hayhurst, M., and McConnell, S.K. (2003). Mouse models of holoprosencephaly. Curr. Opin. Neurol. 16, 135–141, https://doi.org/10.1097/01.wco.0000063761.15877.4010.1097/00019052-200304000-00003.Search in Google Scholar

Heussler, H.S., Suri, M., Young, I.D., and Muenke, M. (2002). Extreme variability of expression of a sonic Hedgehog mutation: attention difficulties and holoprosencephaly. Arch. Dis. Child. 86, 293–296, https://doi.org/10.1136/adc.86.4.293.Search in Google Scholar PubMed PubMed Central

Heyne, G.W., Everson, J.L., Ansen-Wilson, L.J., Melberg, C.G., Fink, D.M., Parins, K.F., Doroodchi, P., Ulschmid, C.M., and Lipinski, R.J. (2016). Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model. Dis. Model. Mech. 9, 1307–1315, https://doi.org/10.1242/dmm.026328.Search in Google Scholar PubMed PubMed Central

Hoch, R.V., Rubenstein, J.L.R., and Pleasure, S. (2009). Genes and signaling events that establish regional patterning of the mammalian forebrain. Semin. Cell Dev. Biol. 20, 378–386, https://doi.org/10.1016/j.semcdb.2009.02.005.Search in Google Scholar PubMed

Hong, M., and Krauss, R.S. (2018). Modeling the complex etiology of holoprosencephaly in mice. Am. J. Med. Genet. C Semin. Med. Genet. 178, 140–150, https://doi.org/10.1002/ajmg.c.31611.Search in Google Scholar PubMed PubMed Central

Hong, M., Srivastava, K., Kim, S., Allen, B.L., Leahy, D.J., Hu, P., Roessler, E., Krauss, R.S., and Muenke, M. (2017). BOC is a modifier gene in holoprosencephaly. Hum. Mutat. 38, 1464–1470, https://doi.org/10.1002/humu.23286.Search in Google Scholar PubMed PubMed Central

Kantarci, S., Al-Gazali, L., Hill, R.S., Donnai, D., Black, G.C.M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., et al.. (2007). Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat. Genet. 39, 957–959, https://doi.org/10.1038/ng2063.Search in Google Scholar PubMed PubMed Central

Khalifa, O., Al-Sahlawi, Z., Imtiaz, F., Ramzan, K., Allam, R., Al-Mostafa, A., Abdel-Fattah, M., Abuharb, G., Nester, M., Verloes, A., et al.. (2015). Variable expression pattern in Donnai-Barrow syndrome: report of two novel LRP2 mutations and review of the literature. Eur. J. Med. Genet. 58, 293–299, https://doi.org/10.1016/j.ejmg.2014.12.008.Search in Google Scholar PubMed

Kim, A., Savary, C., Dubourg, C., Carré, W., Mouden, C., Hamdi-Rozé, H., Guyodo, H., Douce, J.L., Génin, E., Campion, D., et al.. (2019). Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly. Brain 142, 35–49, https://doi.org/10.1093/brain/awy290.Search in Google Scholar PubMed

Kozyraki, R., and Cases, O. (2017). Inherited LRP2 dysfunction in human disease and animal models. J. Rare Dis. Res. Treat. 2, 22–31, https://doi.org/10.29245/2572-9411/2017/5.1122.Search in Google Scholar

Krauss, R.S. (2007). Holoprosencephaly: new models, new insights. Expet Rev. Mol. Med. 9, 1–17, https://doi.org/10.1017/S1462399407000440.Search in Google Scholar PubMed

Krauss, R.S., and Hong, M. (2016). Chapter thirty-three - gene–environment interactions and the etiology of birth defects. In Current Topics in Developmental Biology Essays on Developmental Biology, Part A. P.M. Wassarman, ed. (Academic Press), pp. 569–580.10.1016/bs.ctdb.2015.12.010Search in Google Scholar PubMed

Kur, E., Mecklenburg, N., Cabrera, R.M., Willnow, T.E., and Hammes, A. (2014). LRP2 mediates folate uptake in the developing neural tube. J. Cell Sci. 127, 2261–2268, https://doi.org/10.1242/jcs.140145.Search in Google Scholar PubMed

Leoncini, E., Baranello, G., Orioli, I.M., Annerén, G., Bakker, M., Bianchi, F., Bower, C., Canfield, M.A., Castilla, E.E., Cocchi, G., et al.. (2008). Frequency of holoprosencephaly in the international clearinghouse birth defects surveillance systems: searching for population variations. Birt. Defects Res. A. Clin. Mol. Teratol. 82, 585–591, https://doi.org/10.1002/bdra.20479.Search in Google Scholar PubMed

Li, Y., Klena, N.T., Gabriel, G.C., Liu, X., Kim, A.J., Lemke, K., Chen, Y., Chatterjee, B., Devine, W., Damerla, R.R., et al.. (2015). Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature 521, 520–524, https://doi.org/10.1038/nature14269.Search in Google Scholar PubMed PubMed Central

Lo, H.-F., Hong, M., and Krauss, R.S. (2021). Concepts in multifactorial etiology of developmental disorders: gene-gene and gene-environment interactions in holoprosencephaly. Front. Cell Dev. Biol. 9, 86–95, 795194, https://doi.org/10.3389/fcell.2021.795194.Search in Google Scholar

Longoni, M., Kantarci, S., Donnai, D., Pober, B.R., (1993). Donnai-Barrow syndrome. In GeneReviews®, M.P. Adam, D.B. Everman, G.M. Mirzaa, R.A. Pagon, S.E. Wallace, L.J. Bean, K.W. Gripp, and A. Amemiya, eds. (University of Washington, Seattle).Search in Google Scholar

Ming, J.E., and Muenke, M. (2002). Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am. J. Hum. Genet. 71, 1017–1032, https://doi.org/10.1086/344412.Search in Google Scholar

Mecklenburg, N., Kowalczyk, I., Witte, F., Görne, J., Laier, A., Mamo, T.M., Gonschior, H., Lehmann, M., Richter, M., Sporbert, A., et al.. (2021). Identification of disease-relevant modulators of the SHH pathway in the developing brain. Development 148, dev199307, https://doi.org/10.1242/dev.199307.Search in Google Scholar

Muenke, M., and Beachy, P.A. (2000). Genetics of ventral forebrain development and holoprosencephaly. Curr. Opin. Genet. Dev. 10, 262–269, https://doi.org/10.1016/S0959-437X(00)00084-8.Search in Google Scholar

Muenke, M., and Cohen, M.M. (2000). Genetic approaches to understanding brain development: holoprosencephaly as a model. Ment. Retard. Dev. Disabil. Res. Rev. 6, 152–218, https://doi.org/10.1002/(SICI)1098-277910.1002/(sici)1098-2779(2000)6:1<15::aid-mrdd3>3.0.co;2-8.10.1002/(SICI)1098-2779(2000)6:1<15::AID-MRDD3>3.0.CO;2-8Search in Google Scholar

Nachury, M.V., and Mick, D.U. (2019). Establishing and regulating the composition of cilia for signal transduction. Nat. Rev. Mol. Cell Biol. 20, 389–405, https://doi.org/10.1038/s41580-019-0116-4.Search in Google Scholar

Ohkubo, Y., Chiang, C., and Rubenstein, J.L.R. (2002). Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles. Neuroscience 111, 1–17, https://doi.org/10.1016/S0306-4522(01)00616-9.Search in Google Scholar

Ozdemir, H., Plamondon, J., Gaskin, P., Asoglu, M.R., and Turan, S. (2019). A prenatally diagnosed case of Donnai-Barrow syndrome: highlighting the importance of whole exome sequencing in cases of consanguinity. Am. J. Med. Genet. A., https://doi.org/10.1002/ajmg.a.61428.Search in Google Scholar

Petryk, A., Anderson, R.M., Jarcho, M.P., Leaf, I., Carlson, C.S., Klingensmith, J., Shawlot, W., and O’Connor, M.B. (2004). The mammalian twisted gastrulation gene functions in foregut and craniofacial development. Dev. Biol. 267, 374–386, https://doi.org/10.1016/j.ydbio.2003.11.015.Search in Google Scholar

Pober, B.R., Longoni, M., and Noonan, K.M. (2009). A review of Donnai-Barrow and facio-oculo-acoustico-renal (DB/FOAR) syndrome: clinical features and differential diagnosis. Birt. Defects Res. A. Clin. Mol. Teratol. 85, 76–81, https://doi.org/10.1002/bdra.20534.Search in Google Scholar

Roessler, E., Belloni, E., Gaudenz, K., Jay, P., Berta, P., Scherer, S.W., Tsui, L.-C., and Muenke, M. (1996). Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat. Genet. 14, 357, https://doi.org/10.1038/ng1196-357.Search in Google Scholar PubMed

Rosenfeld, J.A., Ballif, B.C., Martin, D.M., Aylsworth, A.S., Bejjani, B.A., Torchia, B.S., and Shaffer, L.G. (2010). Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE. Hum. Genet. 127, 421–440, https://doi.org/10.1007/s00439-009-0778-7.Search in Google Scholar PubMed

Roessler, E., and Muenke, M. (2010). The molecular genetics of holoprosencephaly. Am. J. Med. Genet. C Semin. Med. Genet. 154C, 52–61, https://doi.org/10.1002/ajmg.c.30236.Search in Google Scholar PubMed PubMed Central

Schachter, K.A., and Krauss, R.S. (2008). Chapter 3 murine models of holoprosencephaly. In Current Topics in Developmental Biology Mouse Models of Developmental Genetic Disease (Academic Press), pp. 139–170.10.1016/S0070-2153(08)00603-0Search in Google Scholar PubMed

Schmidt, S., Luecken, M.D., Trümbach, D., Hembach, S., Niedermeier, K.M., Wenck, N., Pflügler, K., Stautner, C., Böttcher, A., Lickert, H., et al.. (2022). Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease. Nat. Commun. 13, 4819, https://doi.org/10.1038/s41467-022-32229-9.Search in Google Scholar PubMed PubMed Central

Seppala, M., Depew, M.J., Martinelli, D.C., Fan, C.-M., Sharpe, P.T., and Cobourne, M.T. (2007). Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J. Clin. Invest. 117, 1575–1584, https://doi.org/10.1172/JCI32032.Search in Google Scholar PubMed PubMed Central

Shiota, K. (2021). A life-table analysis of the intrauterine fate of malformed human embryos and fetuses. Birth Defects Res. 113, 623–632, https://doi.org/10.1002/bdr2.1888.Search in Google Scholar PubMed

Singla, V., and Reiter, J.F. (2006). The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 313, 629–633, https://doi.org/10.1126/science.1124534.Search in Google Scholar PubMed

Solomon, B.D., Kruszka, P., and Muenke, M. (2018). Holoprosencephaly flashcards: an updated summary for the clinician. Am. J. Med. Genet. C Semin. Med. Genet. 178, 117–121, https://doi.org/10.1002/ajmg.c.31621.Search in Google Scholar PubMed

Spoelgen, R., Hammes, A., Anzenberger, U., Zechner, D., Andersen, O.M., Jerchow, B., and Willnow, T.E. (2005). LRP2/megalin is required for patterning of the ventral telencephalon. Development 132, 405–414, https://doi.org/10.1242/dev.01580.Search in Google Scholar PubMed

Sur, M., and Rubenstein, J.L.R. (2005). Patterning and plasticity of the cerebral cortex. Science 310, 805–810, https://doi.org/10.1126/science.1112070.Search in Google Scholar PubMed

Tekendo-Ngongang, C., Owosela, B., Muenke, M., and Kruszka, P. (2020). Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene-specific. Am. J. Med. Genet. C Semin. Med. Genet. 184, 154–158, https://doi.org/10.1002/ajmg.c.31770.Search in Google Scholar PubMed

Wallis, D.E., and Muenke, M. (1999). Molecular mechanisms of holoprosencephaly. Mol. Genet. Metabol. 68, 126–138, https://doi.org/10.1006/mgme.1999.2895.Search in Google Scholar PubMed

Wallis, D.E., Roessler, E., Hehr, U., Nanni, L., Wiltshire, T., Richieri-Costa, A., Gillessen-Kaesbach, G., Zackai, E.H., Rommens, J., and Muenke, M. (1999). Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat. Genet. 22, 196–198, https://doi.org/10.1038/9718.Search in Google Scholar PubMed

Willnow, T.E., Hilpert, J., Armstrong, S.A., Rohlmann, A., Hammer, R.E., Burns, D.K., and Herz, J. (1996). Defective forebrain development in mice lacking gp330/megalin. Proc. Natl. Acad. Sci. USA 93, 8460–8464, https://doi.org/10.1073/pnas.93.16.8460.Search in Google Scholar PubMed PubMed Central

Zhang, W., Hong, M., Bae, G., Kang, J.-S., and Krauss, R.S. (2011). Boc modifies the holoprosencephaly spectrum of Cdo mutant mice. Dis. Model. Mech. 4, 368–380, https://doi.org/10.1242/dmm.005744.Search in Google Scholar PubMed PubMed Central

Zhang, W., Kang, J.-S., Cole, F., Yi, M.-J., and Krauss, R.S. (2006). Cdo functions at multiple points in the sonic hedgehog pathway, and cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 10, 657–665, https://doi.org/10.1016/j.devcel.2006.04.005.Search in Google Scholar PubMed

Published Online: 2022-10-24
Published in Print: 2022-11-25

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Neuroforum: vom gedruckten Heft ins elektronische Zeitalter
  4. Review articles
  5. The visual representation of space in the primate brain
  6. MicroRNAs in the auditory system: tiny molecules with big impact
  7. Non-coding repeat expansions associated with familial adult myoclonic epilepsy: a new paradigm of gene-independent monogenic disorders
  8. Forebrain development–an intricate balance decides between health and disease
  9. Presentation of scientific institutions
  10. Collaborative Research Centre (CRC 1451) “Key mechanisms of motor control in health and disease”
  11. Collaborative Research Center SFB 1528 “Cognition of Interaction”
  12. SPP2411: ‘Sensing LOOPS: cortico-subcortical interactions for adaptive sensing’
  13. Newly DFG-funded research training group at the University of Kassel: “Biological clocks on multiple time scales” GRK 2749/1
  14. Nachrichten
  15. Catching up in Cologne – 31st Neurobiology Doctoral Students Workshop in Cologne
  16. Nachrichten aus der Gesellschaft
  17. Nachrichten aus der Gesellschaft
https://doi.org/10.1515/nf-2022-0023
Keywords for this article
congenital disorder; genetic modifier; holoprosencephaly; primary cilium; sonic hedgehog signaling

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Neuroforum: vom gedruckten Heft ins elektronische Zeitalter
  4. Review articles
  5. The visual representation of space in the primate brain
  6. MicroRNAs in the auditory system: tiny molecules with big impact
  7. Non-coding repeat expansions associated with familial adult myoclonic epilepsy: a new paradigm of gene-independent monogenic disorders
  8. Forebrain development–an intricate balance decides between health and disease
  9. Presentation of scientific institutions
  10. Collaborative Research Centre (CRC 1451) “Key mechanisms of motor control in health and disease”
  11. Collaborative Research Center SFB 1528 “Cognition of Interaction”
  12. SPP2411: ‘Sensing LOOPS: cortico-subcortical interactions for adaptive sensing’
  13. Newly DFG-funded research training group at the University of Kassel: “Biological clocks on multiple time scales” GRK 2749/1
  14. Nachrichten
  15. Catching up in Cologne – 31st Neurobiology Doctoral Students Workshop in Cologne
  16. Nachrichten aus der Gesellschaft
  17. Nachrichten aus der Gesellschaft
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 25.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/nf-2022-0023/html
Scroll to top button