Opposing effects of CREBBP mutations govern the phenotype of Rubinstein-Taybi syndrome and adult SHH medulloblastoma / Daniel J. Merk, Jasmin Ohli, Natalie D. Merk, Venu Thatikonda, Sorana Morrissy, Melanie Schoof, Susanne N. Schmid, Luke Harrison, Severin Filser, Julia Ahlfeld, Serap Erkek, Kaamini Raithatha, Thomas Andreska, Marc Weißhaar, Michael Launspach, Julia E. Neumann, Mehdi Shakarami, Dennis Plenker, Marco A. Marra, Yisu Li, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J. M. Jones, Beat Lutz, Birgit Ertl-Wagner, Andrea Rossi, Rabea Wagener, Reiner Siebert, Andreas Jung, Charles G. Eberhart, Boleslaw Lach, Michael Sendtner, Stefan M. Pfister, Michael D. Taylor, Lukas Chavez, Marcel Kool, and Ulrich Schüller
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
March 15, 2018 2018 |
|---|---|
| Erschienen: |
March 15, 2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:44 |
|---|---|
| Enthalten in: |
Developmental cell - 44(2018), 6, Seite 709-724, e1-e6 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Merk, Daniel J. [VerfasserIn] |
|---|
| Links: |
Volltext [lizenzpflichtig] |
|---|
| Anmerkungen: |
Gesehen am 06.04.2020 |
|---|
| Umfang: |
23 |
|---|
| doi: |
10.1016/j.devcel.2018.02.012 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
1694124002 |
|---|
| LEADER | 01000caa a2200265 4500 | ||
|---|---|---|---|
| 001 | 1694124002 | ||
| 003 | DE-627 | ||
| 005 | 20230427100441.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200406s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.devcel.2018.02.012 |2 doi | |
| 035 | |a (DE-627)1694124002 | ||
| 035 | |a (DE-599)KXP1694124002 | ||
| 035 | |a (OCoLC)1341313900 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 100 | 1 | |a Merk, Daniel J. |e verfasserin |0 (DE-588)1207789496 |0 (DE-627)1694126269 |4 aut | |
| 245 | 1 | 0 | |a Opposing effects of CREBBP mutations govern the phenotype of Rubinstein-Taybi syndrome and adult SHH medulloblastoma |c Daniel J. Merk, Jasmin Ohli, Natalie D. Merk, Venu Thatikonda, Sorana Morrissy, Melanie Schoof, Susanne N. Schmid, Luke Harrison, Severin Filser, Julia Ahlfeld, Serap Erkek, Kaamini Raithatha, Thomas Andreska, Marc Weißhaar, Michael Launspach, Julia E. Neumann, Mehdi Shakarami, Dennis Plenker, Marco A. Marra, Yisu Li, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J. M. Jones, Beat Lutz, Birgit Ertl-Wagner, Andrea Rossi, Rabea Wagener, Reiner Siebert, Andreas Jung, Charles G. Eberhart, Boleslaw Lach, Michael Sendtner, Stefan M. Pfister, Michael D. Taylor, Lukas Chavez, Marcel Kool, and Ulrich Schüller |
| 264 | 1 | |c March 15, 2018 | |
| 300 | |a 23 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 06.04.2020 | ||
| 520 | |a Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. | ||
| 650 | 4 | |a acetyltransferase | |
| 650 | 4 | |a Acetyltransferases | |
| 650 | 4 | |a Adult | |
| 650 | 4 | |a Animals | |
| 650 | 4 | |a Cerebellar Neoplasms | |
| 650 | 4 | |a cerebellum | |
| 650 | 4 | |a CREB-Binding Protein | |
| 650 | 4 | |a CREBBP | |
| 650 | 4 | |a development | |
| 650 | 4 | |a Female | |
| 650 | 4 | |a Hedgehog Proteins | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Medulloblastoma | |
| 650 | 4 | |a Mice | |
| 650 | 4 | |a Mice, Knockout | |
| 650 | 4 | |a Mutation | |
| 650 | 4 | |a Neurons | |
| 650 | 4 | |a Phenotype | |
| 650 | 4 | |a Rubinstein-Taybi syndrome | |
| 650 | 4 | |a Rubinstein-Taybi Syndrome | |
| 650 | 4 | |a SHH medulloblastoma | |
| 650 | 4 | |a Signal Transduction | |
| 700 | 1 | |a Ohli, Jasmin |e verfasserin |4 aut | |
| 700 | 1 | |a Merk, Natalie D. |e verfasserin |4 aut | |
| 700 | 1 | |a Thatikonda, Venu |e verfasserin |4 aut | |
| 700 | 1 | |a Morrissy, Sorana |e verfasserin |4 aut | |
| 700 | 1 | |a Schoof, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Schmid, Susanne N. |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Luke |e verfasserin |4 aut | |
| 700 | 1 | |a Filser, Severin |e verfasserin |4 aut | |
| 700 | 1 | |a Ahlfeld, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Erkek, Serap |e verfasserin |0 (DE-588)1181719321 |0 (DE-627)1662328389 |4 aut | |
| 700 | 1 | |a Raithatha, Kaamini |e verfasserin |4 aut | |
| 700 | 1 | |a Andreska, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Weißhaar, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Launspach, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Neumann, Julia E. |e verfasserin |4 aut | |
| 700 | 1 | |a Shakarami, Mehdi |e verfasserin |4 aut | |
| 700 | 1 | |a Plenker, Dennis |e verfasserin |4 aut | |
| 700 | 1 | |a Marra, Marco A. |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yisu |e verfasserin |4 aut | |
| 700 | 1 | |a Mungall, Andrew J. |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Richard A. |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yussanne |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Steven J. M. |e verfasserin |4 aut | |
| 700 | 1 | |a Lutz, Beat |e verfasserin |4 aut | |
| 700 | 1 | |a Ertl-Wagner, Birgit |e verfasserin |4 aut | |
| 700 | 1 | |a Rossi, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Wagener, Rabea |e verfasserin |4 aut | |
| 700 | 1 | |a Siebert, Reiner |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Eberhart, Charles G. |e verfasserin |4 aut | |
| 700 | 1 | |a Lach, Boleslaw |e verfasserin |4 aut | |
| 700 | 1 | |a Sendtner, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Pfister, Stefan |d 1974- |e verfasserin |0 (DE-588)123850215 |0 (DE-627)706450930 |0 (DE-576)293908400 |4 aut | |
| 700 | 1 | |a Taylor, Michael D. |e verfasserin |4 aut | |
| 700 | 1 | |a Chavez, Lukas |e verfasserin |4 aut | |
| 700 | 1 | |a Kool, Marcel |e verfasserin |4 aut | |
| 700 | 1 | |a Schüller, Ulrich |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Developmental cell |d Cambridge, Mass. : Cell Press, 2001 |g 44(2018), 6, Seite 709-724, e1-e6 |h Online-Ressource |w (DE-627)332622827 |w (DE-600)2053870-4 |w (DE-576)096930357 |x 1878-1551 |7 nnns |
| 773 | 1 | 8 | |g volume:44 |g year:2018 |g number:6 |g pages:709-724, e1-e6 |g extent:23 |
| 856 | 4 | 0 | |u https://doi.org/10.1016/j.devcel.2018.02.012 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_U | ||
| 912 | |a GBV_ILN_2013 | ||
| 912 | |a ISIL_DE-16-250 | ||
| 912 | |a SYSFLAG_1 | ||
| 912 | |a GBV_KXP | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a GBV_ILN_20 | ||
| 912 | |a GBV_ILN_22 | ||
| 912 | |a GBV_ILN_23 | ||
| 912 | |a GBV_ILN_24 | ||
| 912 | |a GBV_ILN_31 | ||
| 912 | |a GBV_ILN_39 | ||
| 912 | |a GBV_ILN_40 | ||
| 912 | |a GBV_ILN_60 | ||
| 912 | |a GBV_ILN_62 | ||
| 912 | |a GBV_ILN_63 | ||
| 912 | |a GBV_ILN_65 | ||
| 912 | |a GBV_ILN_69 | ||
| 912 | |a GBV_ILN_70 | ||
| 912 | |a GBV_ILN_73 | ||
| 912 | |a GBV_ILN_74 | ||
| 912 | |a GBV_ILN_95 | ||
| 912 | |a GBV_ILN_105 | ||
| 912 | |a GBV_ILN_110 | ||
| 912 | |a GBV_ILN_151 | ||
| 912 | |a GBV_ILN_161 | ||
| 912 | |a GBV_ILN_170 | ||
| 912 | |a GBV_ILN_206 | ||
| 912 | |a GBV_ILN_213 | ||
| 912 | |a GBV_ILN_230 | ||
| 912 | |a GBV_ILN_285 | ||
| 912 | |a GBV_ILN_293 | ||
| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_702 | ||
| 912 | |a GBV_ILN_2011 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_2015 | ||
| 912 | |a GBV_ILN_2190 | ||
| 912 | |a GBV_ILN_2446 | ||
| 912 | |a GBV_ILN_4012 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4125 | ||
| 912 | |a GBV_ILN_4126 | ||
| 912 | |a GBV_ILN_4249 | ||
| 912 | |a GBV_ILN_4305 | ||
| 912 | |a GBV_ILN_4306 | ||
| 912 | |a GBV_ILN_4307 | ||
| 912 | |a GBV_ILN_4313 | ||
| 912 | |a GBV_ILN_4322 | ||
| 912 | |a GBV_ILN_4323 | ||
| 912 | |a GBV_ILN_4324 | ||
| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4338 | ||
| 912 | |a GBV_ILN_4367 | ||
| 912 | |a GBV_ILN_4700 | ||
| 936 | u | w | |d 44 |j 2018 |e 6 |h 709-724, e1-e6 |g 23 |
| 951 | |a AR | ||
| 952 | |d 44 |j 2018 |e 6 |h 709-724, e1-e6 |g 23 | ||
| 980 | |2 2013 |1 01 |x DE-16-250 |b 3618969996 |c 00 |f --%%-- |d --%%-- |e --%%-- |j --%%-- |y l01 |z 06-04-20 | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 00 |s s |a hd2018 | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 01 |s s |0 (DE-627)1410508463 |a wissenschaftlicher Artikel (Zeitschrift) | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 02 |s s |a per_38 | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 03 |s s |a s_23 | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 04 |s p |0 (DE-627)1464593051 |a Pfister, Stefan | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 04 |s k |0 (DE-627)1416740988 |a Zentrum für Kinder- und Jugendmedizin | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 04 |s s |0 (DE-627)1410501914 |a Verfasser | ||
| 982 | |2 2013 |1 01 |x DE-16-250 |8 04 |s s |a pos_34 | ||