Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
Abstract Background The cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the externa...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-02-01
|
| Series: | Neural Development |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13064-019-0128-y |
| _version_ | 1818508197057527808 |
|---|---|
| author | Alexandre Wojcinski Morgane Morabito Andrew K. Lawton Daniel N. Stephen Alexandra L. Joyner |
| author_facet | Alexandre Wojcinski Morgane Morabito Andrew K. Lawton Daniel N. Stephen Alexandra L. Joyner |
| author_sort | Alexandre Wojcinski |
| collection | DOAJ |
| description | Abstract Background The cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing cerebellum and could lead to mis-interpretation of phenotypes was not known. Methods We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) Our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Results Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved. Conclusion We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe cerebellum hypoplasia. The ability of the neonatal cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of Atoh1-Cre conditional mutants affecting GCPs. |
| first_indexed | 2024-12-10T22:28:22Z |
| format | Article |
| id | doaj.art-c247cdeab8ef43fc9c69d770519b58a7 |
| institution | Directory Open Access Journal |
| issn | 1749-8104 |
| language | English |
| last_indexed | 2024-12-10T22:28:22Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Neural Development |
| spelling | doaj.art-c247cdeab8ef43fc9c69d770519b58a72022-12-22T01:31:07ZengBMCNeural Development1749-81042019-02-0114111510.1186/s13064-019-0128-yGenetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitorsAlexandre Wojcinski0Morgane Morabito1Andrew K. Lawton2Daniel N. Stephen3Alexandra L. Joyner4Developmental Biology Program, Sloan Kettering InstituteDevelopmental Biology Program, Sloan Kettering InstituteDevelopmental Biology Program, Sloan Kettering InstituteDevelopmental Biology Program, Sloan Kettering InstituteDevelopmental Biology Program, Sloan Kettering InstituteAbstract Background The cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing cerebellum and could lead to mis-interpretation of phenotypes was not known. Methods We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) Our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Results Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved. Conclusion We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe cerebellum hypoplasia. The ability of the neonatal cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of Atoh1-Cre conditional mutants affecting GCPs.http://link.springer.com/article/10.1186/s13064-019-0128-yCerebellumSHH signalingGLI2Nestin-expressing progenitorsNeurogenesisAtoh1-Cre |
| spellingShingle | Alexandre Wojcinski Morgane Morabito Andrew K. Lawton Daniel N. Stephen Alexandra L. Joyner Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors Neural Development Cerebellum SHH signaling GLI2 Nestin-expressing progenitors Neurogenesis Atoh1-Cre |
| title | Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors |
| title_full | Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors |
| title_fullStr | Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors |
| title_full_unstemmed | Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors |
| title_short | Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors |
| title_sort | genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone derived progenitors |
| topic | Cerebellum SHH signaling GLI2 Nestin-expressing progenitors Neurogenesis Atoh1-Cre |
| url | http://link.springer.com/article/10.1186/s13064-019-0128-y |
| work_keys_str_mv | AT alexandrewojcinski geneticdeletionofgenesinthecerebellarrhombicliplineagecanstimulatecompensationthroughadaptivereprogrammingofventricularzonederivedprogenitors AT morganemorabito geneticdeletionofgenesinthecerebellarrhombicliplineagecanstimulatecompensationthroughadaptivereprogrammingofventricularzonederivedprogenitors AT andrewklawton geneticdeletionofgenesinthecerebellarrhombicliplineagecanstimulatecompensationthroughadaptivereprogrammingofventricularzonederivedprogenitors AT danielnstephen geneticdeletionofgenesinthecerebellarrhombicliplineagecanstimulatecompensationthroughadaptivereprogrammingofventricularzonederivedprogenitors AT alexandraljoyner geneticdeletionofgenesinthecerebellarrhombicliplineagecanstimulatecompensationthroughadaptivereprogrammingofventricularzonederivedprogenitors |