{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:00:38Z","timestamp":1791327638463,"version":"4.3.1"},"reference-count":51,"publisher":"The Company of Biologists","issue":"21","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,11,1]]},"abstract":"<jats:p>Holoprosencephaly (HPE) is a devastating forebrain abnormality with a range of morphological defects characterized by loss of midline tissue. In the telencephalon, the embryonic precursor of the cerebral hemispheres,specialized cell types form a midline that separates the hemispheres. In the present study, deletion of the BMP receptor genes, Bmpr1b and Bmpr1a, in the mouse telencephalon results in a loss of all dorsal midline cell types without affecting the specification of cortical and ventral precursors. In the holoprosencephalic Shh-\/- mutant, by contrast, ventral patterning is disrupted, whereas the dorsal midline initially forms. This suggests that two separate developmental mechanisms can underlie the ontogeny of HPE. The Bmpr1a;Bmpr1b mutant provides a model for a subclass of HPE in humans: midline inter-hemispheric HPE.<\/jats:p>","DOI":"10.1242\/dev.004325","type":"journal-article","created":{"date-parts":[[2007,10,4]],"date-time":"2007-10-04T00:26:02Z","timestamp":1191457562000},"page":"3789-3794","source":"Crossref","is-referenced-by-count":99,"title":["Mutations in the BMP pathway in mice support the existence of two molecular classes of holoprosencephaly"],"prefix":"10.1242","volume":"134","author":[{"given":"Marie","family":"Fernandes","sequence":"first","affiliation":[{"name":"Departments of Neuroscience and Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grigoriy","family":"Gutin","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Alcorn","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10021,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan K.","family":"McConnell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Stanford University, Stanford, CA,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean M.","family":"He\u0301bert","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042621054559700_REF1","doi-asserted-by":"crossref","unstructured":"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. Development129,4975-4987.","DOI":"10.1242\/dev.129.21.4975"},{"key":"2021042621054559700_REF2","doi-asserted-by":"crossref","unstructured":"Aoto, K., Nishimura, T., Eto, K. and Motoyama, J.(2002). Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev. Biol.251,320-332.","DOI":"10.1006\/dbio.2002.0811"},{"key":"2021042621054559700_REF3","unstructured":"Barkovich, A. J. and Quint, D. J. (1993). Middle interhemispheric fusion: an unusual variant of holoprosencephaly. AJNR Am. J. Neuroradiol.14,431-440."},{"key":"2021042621054559700_REF4","doi-asserted-by":"crossref","unstructured":"Blackshear, P. J., Graves, J. P., Stumpo, D. J., Cobos, I.,Rubenstein, J. L. and Zeldin, D. C. (2003). Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4. Development130,4539-4552.","DOI":"10.1242\/dev.00661"},{"key":"2021042621054559700_REF5","doi-asserted-by":"crossref","unstructured":"Brown, L. Y., Odent, S., David, V., Blayau, M., Dubourg, C.,Apacik, C., Delgado, M. A., Hall, B. D., Reynolds, J. F., Sommer, A. et al. (2001). Holoprosencephaly due to mutations in ZIC2:alanine tract expansion mutations may be caused by parental somatic recombination. Hum. Mol. Genet.10,791-796.","DOI":"10.1093\/hmg\/10.8.791"},{"key":"2021042621054559700_REF6","doi-asserted-by":"crossref","unstructured":"Cheng, X., Hsu, C. M., Currle, D. S., Hu, J. S., Barkovich, A. J. and Monuki, E. S. (2006). Central roles of the roof plate in telencephalic development and holoprosencephaly. J. Neurosci.26,7640-7649.","DOI":"10.1523\/JNEUROSCI.0714-06.2006"},{"key":"2021042621054559700_REF7","doi-asserted-by":"crossref","unstructured":"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. Nature383,407-413.","DOI":"10.1038\/383407a0"},{"key":"2021042621054559700_REF8","doi-asserted-by":"crossref","unstructured":"Crossley, P. H. and Martin, G. R. (1995). The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development121,439-451.","DOI":"10.1242\/dev.121.2.439"},{"key":"2021042621054559700_REF9","doi-asserted-by":"crossref","unstructured":"Crossley, P. H., Martinez, S., Ohkubo, Y. and Rubenstein, J. L. (2001). Coordinate expression of Fgf8, Otx2, Bmp4, and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles. Neuroscience108,183-206.","DOI":"10.1016\/S0306-4522(01)00411-0"},{"key":"2021042621054559700_REF10","doi-asserted-by":"crossref","unstructured":"Derynck, R. and Zhang, Y. E. (2003). Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature425,577-584.","DOI":"10.1038\/nature02006"},{"key":"2021042621054559700_REF11","doi-asserted-by":"crossref","unstructured":"Frantz, G. D., Weimann, J. M., Levin, M. E. and McConnell, S. K. (1994). Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum. J. Neurosci.14,5725-5740.","DOI":"10.1523\/JNEUROSCI.14-10-05725.1994"},{"key":"2021042621054559700_REF12","doi-asserted-by":"crossref","unstructured":"Furuta, Y., Piston, D. W. and Hogan, B. L.(1997). Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development124,2203-2212.","DOI":"10.1242\/dev.124.11.2203"},{"key":"2021042621054559700_REF13","doi-asserted-by":"crossref","unstructured":"Grove, E. A., Tole, S., Limon, J., Yip, L. and Ragsdale, C. W. (1998). The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development125,2315-2325.","DOI":"10.1242\/dev.125.12.2315"},{"key":"2021042621054559700_REF14","doi-asserted-by":"crossref","unstructured":"Gunhaga, L., Marklund, M., Sjodal, M., Hsieh, J. C., Jessell, T. M. and Edlund, T. (2003). Specification of dorsal telencephalic character by sequential Wnt and FGF signaling. Nat. Neurosci.6,701-707.","DOI":"10.1038\/nn1068"},{"key":"2021042621054559700_REF15","doi-asserted-by":"crossref","unstructured":"Gutin, G., Fernandes, M., Palazzolo, L., Paek, H., Yu, K.,Ornitz, D. M., McConnell, S. K. and Hebert, J. M. (2006). FGF signalling generates ventral telencephalic cells independently of SHH. Development133,2937-2946.","DOI":"10.1242\/dev.02465"},{"key":"2021042621054559700_REF16","doi-asserted-by":"crossref","unstructured":"Hayhurst, M. and McConnell, S. K. (2003). Mouse models of holoprosencephaly. Curr. Opin. Neurol.16,135-141.","DOI":"10.1097\/00019052-200304000-00003"},{"key":"2021042621054559700_REF17","doi-asserted-by":"crossref","unstructured":"Hebert, J. M. and McConnell, S. K. (2000). Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev. Biol.222,296-306.","DOI":"10.1006\/dbio.2000.9732"},{"key":"2021042621054559700_REF18","doi-asserted-by":"crossref","unstructured":"Hebert, J. M., Mishina, Y. and McConnell, S. K.(2002). BMP signaling is required locally to pattern the dorsal telencephalic midline. Neuron35,1029-1041.","DOI":"10.1016\/S0896-6273(02)00900-5"},{"key":"2021042621054559700_REF19","unstructured":"Hirabayashi, Y., Itoh, Y., Tabata, H., Nakajima, K., Akiyama,T., Masuyama, N. and Gotoh, Y. (2004). The Wnt\/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development131,2791-2801."},{"key":"2021042621054559700_REF20","doi-asserted-by":"crossref","unstructured":"Hsieh-Li, H. M., Witte, D. P., Szucsik, J. C., Weinstein, M.,Li, H. and Potter, S. S. (1995). Gsh-2, a murine homeobox gene expressed in the developing brain. Mech. Dev.50,177-186.","DOI":"10.1016\/0925-4773(94)00334-J"},{"key":"2021042621054559700_REF21","doi-asserted-by":"crossref","unstructured":"Jones, C. M., Lyons, K. M. and Hogan, B. L.(1991). Involvement of Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse. Development111,531-542.","DOI":"10.1242\/dev.111.2.531"},{"key":"2021042621054559700_REF22","doi-asserted-by":"crossref","unstructured":"Kuschel, S., Ruther, U. and Theil, T. (2003). A disrupted balance between Bmp\/Wnt and Fgf signaling underlies the ventralization of the Gli3 mutant telencephalon. Dev. Biol.260,484-495.","DOI":"10.1016\/S0012-1606(03)00252-5"},{"key":"2021042621054559700_REF23","doi-asserted-by":"crossref","unstructured":"Lee, S. M., Tole, S., Grove, E. and McMahon, A. P.(2000). A local Wnt-3a signal is required for development of the mammalian hippocampus. Development127,457-467.","DOI":"10.1242\/dev.127.3.457"},{"key":"2021042621054559700_REF24","doi-asserted-by":"crossref","unstructured":"Marcorelles, P., Loget, P., Fallet-Bianco, C., Roume, J.,Encha-Razavi, F. and Delezoide, A. L. (2002). Unusual variant of holoprosencephaly in monosomy 13q. Pediatr. Dev. Pathol.5,170-178.","DOI":"10.1007\/s10024001-0200-5"},{"key":"2021042621054559700_REF25","doi-asserted-by":"crossref","unstructured":"Mehler, M. F., Mabie, P. C., Zhu, G., Gokhan, S. and Kessler, J. A. (2000). Developmental changes in progenitor cell responsiveness to bone morphogenetic proteins differentially modulate progressive CNS lineage fate. Dev. Neurosci.22, 74-85.","DOI":"10.1159\/000017429"},{"key":"2021042621054559700_REF26","doi-asserted-by":"crossref","unstructured":"Ming, J. E. and Muenke, M. (2002). Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am. J. Hum. Genet.71,1017-1032.","DOI":"10.1086\/344412"},{"key":"2021042621054559700_REF27","doi-asserted-by":"crossref","unstructured":"Mishina, Y., Hanks, M. C., Miura, S., Tallquist, M. D. and Behringer, R. R. (2002). Generation of Bmpr\/Alk3 conditional knockout mice. Genesis32, 69-72.","DOI":"10.1002\/gene.10038"},{"key":"2021042621054559700_REF28","doi-asserted-by":"crossref","unstructured":"Monuki, E. S., Porter, F. D. and Walsh, C. A.(2001). Patterning of the dorsal telencephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron32,591-604.","DOI":"10.1016\/S0896-6273(01)00504-9"},{"key":"2021042621054559700_REF29","doi-asserted-by":"crossref","unstructured":"Muenke, M. and Beachy, P. A. (2000). Genetics of ventral forebrain development and holoprosencephaly. Curr. Opin. Genet. Dev.10,262-269.","DOI":"10.1016\/S0959-437X(00)00084-8"},{"key":"2021042621054559700_REF30","doi-asserted-by":"crossref","unstructured":"Nagai, T., Aruga, J., Minowa, O., Sugimoto, T., Ohno, Y., Noda,T. and Mikoshiba, K. (2000). Zic2 regulates the kinetics of neurulation. Proc. Natl. Acad. Sci. USA97,1618-1623.","DOI":"10.1073\/pnas.97.4.1618"},{"key":"2021042621054559700_REF31","doi-asserted-by":"crossref","unstructured":"Nanni, L., Ming, J. E., Bocian, M., Steinhaus, K., Bianchi, D. W., Die-Smulders, C., Giannotti, A., Imaizumi, K., Jones, K. L., Campo, M. D. et al. (1999). The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum. Mol. Genet.8,2479-2488.","DOI":"10.1093\/hmg\/8.13.2479"},{"key":"2021042621054559700_REF32","doi-asserted-by":"crossref","unstructured":"Ohkubo, Y., Chiang, C. and Rubenstein, J. L.(2002). Coordinate regulation and synergistic actions of BMP4,SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles. Neuroscience111, 1-17.","DOI":"10.1016\/S0306-4522(01)00616-9"},{"key":"2021042621054559700_REF33","doi-asserted-by":"crossref","unstructured":"Pabst, O., Herbrand, H., Takuma, N. and Arnold, H. H.(2000). NKX2 gene expression in neuroectoderm but not in mesendodermally derived structures depends on sonic hedgehog in mouse embryos. Dev. Genes Evol.210,47-50.","DOI":"10.1007\/PL00008188"},{"key":"2021042621054559700_REF34","doi-asserted-by":"crossref","unstructured":"Panchision, D. M., Pickel, J. M., Studer, L., Lee, S. H.,Turner, P. A., Hazel, T. G. and McKay, R. D. (2001). Sequential actions of BMP receptors control neural precursor cell production and fate. Genes Dev.15,2094-2110.","DOI":"10.1101\/gad.894701"},{"key":"2021042621054559700_REF35","doi-asserted-by":"crossref","unstructured":"Park, H. L., Bai, C., Platt, K. A., Matise, M. P., Beeghly, A.,Hui, C. C., Nakashima, M. and Joyner, A. L. (2000). Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development127,1593-1605.","DOI":"10.1242\/dev.127.8.1593"},{"key":"2021042621054559700_REF36","doi-asserted-by":"crossref","unstructured":"Rallu, M., Machold, R., Gaiano, N., Corbin, J. G., McMahon, A. P. and Fishell, G. (2002). Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling. Development129,4963-4974.","DOI":"10.1242\/dev.129.21.4963"},{"key":"2021042621054559700_REF37","doi-asserted-by":"crossref","unstructured":"Rash, B. G. and Grove, E. A. (2007). Patterning the dorsal telencephalon: a role for Sonic Hedgehog. J. Neurosci. (in press).","DOI":"10.1523\/JNEUROSCI.3204-07.2007"},{"key":"2021042621054559700_REF38","doi-asserted-by":"crossref","unstructured":"Rattner, A., Hsieh, J. C., Smallwood, P. M., Gilbert, D. J.,Copeland, N. G., Jenkins, N. A. and Nathans, J. (1997). A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc. Natl. Acad. Sci. USA94,2859-2863.","DOI":"10.1073\/pnas.94.7.2859"},{"key":"2021042621054559700_REF39","doi-asserted-by":"crossref","unstructured":"Rodriguez-Esteban, C., Schwabe, J. W., Pena, J. D.,Rincon-Limas, D. E., Magallon, J., Botas, J. and Belmonte, J. C.(1998). Lhx2, a vertebrate homologue of apterous, regulates vertebrate limb outgrowth. Development125,3925-3934.","DOI":"10.1242\/dev.125.20.3925"},{"key":"2021042621054559700_REF40","doi-asserted-by":"crossref","unstructured":"Shimamura, K., Hartigan, D. J., Martinez, S., Puelles, L. and Rubenstein, J. L. (1995). Longitudinal organization of the anterior neural plate and neural tube. Development121,3923-3933.","DOI":"10.1242\/dev.121.12.3923"},{"key":"2021042621054559700_REF41","doi-asserted-by":"crossref","unstructured":"Shimogori, T., Banuchi, V., Ng, H. Y., Strauss, J. B. and Grove,E. A. (2004). Embryonic signaling centers expressing BMP, WNT and FGF proteins interact to pattern the cerebral cortex. Development131,5639-5647.","DOI":"10.1242\/dev.01428"},{"key":"2021042621054559700_REF42","unstructured":"Simon, E. M., Hevner, R. F., Pinter, J. D., Clegg, N. J.,Delgado, M., Kinsman, S. L., Hahn, J. S. and Barkovich, A. J.(2002). The middle interhemispheric variant of holoprosencephaly. AJNR Am. J. Neuroradiol.23,151-156."},{"key":"2021042621054559700_REF43","doi-asserted-by":"crossref","unstructured":"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. Development132,405-414.","DOI":"10.1242\/dev.01580"},{"key":"2021042621054559700_REF44","doi-asserted-by":"crossref","unstructured":"Storm, E. E., Garel, S., Borello, U., Hebert, J. M., Martinez,S., McConnell, S. K., Martin, G. R. and Rubenstein, J. L.(2006). Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development133,1831-1844.","DOI":"10.1242\/dev.02324"},{"key":"2021042621054559700_REF45","doi-asserted-by":"crossref","unstructured":"Tao, W. and Lai, E. (1992). Telencephalon-restricted expression of BF-1, a new member of the HNF-3\/fork head gene family, in the developing rat brain. Neuron8, 957-966.","DOI":"10.1016\/0896-6273(92)90210-5"},{"key":"2021042621054559700_REF46","doi-asserted-by":"crossref","unstructured":"ten Dijke, P., Korchynskyi, O., Valdimarsdottir, G. and Goumans,M. J. (2003). Controlling cell fate by bone morphogenetic protein receptors. Mol. Cell. Endocrinol.211,105-113.","DOI":"10.1016\/j.mce.2003.09.016"},{"key":"2021042621054559700_REF47","doi-asserted-by":"crossref","unstructured":"Theil, T., Alvarez-Bolado, G., Walter, A. and Ruther, U.(1999). Gli3 is required for Emx gene expression during dorsal telencephalon development. Development126,3561-3571.","DOI":"10.1242\/dev.126.16.3561"},{"key":"2021042621054559700_REF48","unstructured":"Theil, T., Aydin, S., Koch, S., Grotewold, L. and Ruther, U.(2002). Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development129,3045-3054."},{"key":"2021042621054559700_REF49","doi-asserted-by":"crossref","unstructured":"Wallis, D. and Muenke, M. (2000). Mutations in holoprosencephaly. Hum. Mutat.16, 99-108.","DOI":"10.1002\/1098-1004(200008)16:2<99::AID-HUMU2>3.0.CO;2-0"},{"key":"2021042621054559700_REF50","doi-asserted-by":"crossref","unstructured":"Walther, C. and Gruss, P. (1991). Pax-6, a murine paired box gene, is expressed in the developing CNS. Development113,1435-1449.","DOI":"10.1242\/dev.113.4.1435"},{"key":"2021042621054559700_REF51","doi-asserted-by":"crossref","unstructured":"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. Cell10,657-665.","DOI":"10.1016\/j.devcel.2006.04.005"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/134\/21\/3789\/1155408\/3789.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/134\/21\/3789\/1155408\/3789.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,14]],"date-time":"2023-05-14T09:38:30Z","timestamp":1684057110000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/134\/21\/3789\/64586\/Mutations-in-the-BMP-pathway-in-mice-support-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,11,1]]},"references-count":51,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2007,11,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.004325","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2007,11,1]]}}}