Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip
© Machold et al; licensee BioMed Central Ltd. 2007
Received: 18 August 2006
Accepted: 23 February 2007
Published: 23 February 2007
During the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere 1 that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known.
Employing both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression.
Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.
The mammalian cerebellum develops from neural progenitors within dorsal rhombomere 1 (r1) just caudal to the mid-hindbrain boundary and above the opening of the fourth ventricle. In the mouse embryonic brain, closure of the neural tube at around embryonic day 9.5 (E9.5) generally creates a ventricular zone of neural progenitors that give rise to successive waves of differentiating neurons; however, at the opening of the fourth ventricle the neuroepithelium extends directly to the roof plate, resulting in an edge along the cerebellar and hindbrain neural plate (r1–r8) termed the rhombic lip. Located at the caudal boundary of the cerebellar anlage in dorsal r1, the cerebellar rhombic lip is a unique germinal territory that gives rise to granule cells and other neurons of the cerebellum and hindbrain [1–4].
Immediately following neural tube closure, the expression of the mouse Atonal homolog Math1 , a basic helix-loop-helix (bHLH) transcription factor that is required for the granule cell lineage and other rhombic lip derived neuronal populations [6–8], begins to be induced in rhombic lip cells that subsequently migrate away from the rhombic lip rostrally over the dorsal surface of the cerebellar anlage [9–11]. The roof plate is required for these events [12–14], and is a source of bone morphogenetic protein (BMP) family members that have been shown to be sufficient to induce cerebellar progenitors to express Math1 in vitro . Furthermore, mouse embryos lacking BMP receptor expression in the neural tube lose Math1 expression in the rhombic lip , indicating a crucial role for BMP signaling in the ongoing induction of Math1 during rhombic lip neurogenesis.
A variety of fate mapping approaches have led to the conclusion that the cerebellar rhombic lip produces temporally distinct neuronal populations during embryogenesis [11, 17, 18]. Recently, we have generated a temporal fate map of the Math1 cells of the cerebellar rhombic lip, using transgenesis in mice to label cohorts of Math1 cells by expressing an inducible Cre recombinase (CreERT2) under the control of the Math1 enhancer. We and others have reported that, prior to emergence of granule cell precursors, the cerebellar rhombic lip is the germinal origin of specific hindbrain and deep cerebellar neurons [7, 8]. Here, we propose that, throughout the peak period of neurogenesis in the rhombic lip (E9.5 to E16.5), there is an ongoing BMP-mediated induction of Math1 in cerebellar progenitors that produces waves of distinct neuronal populations over time. Both the presence of Notch responsive genes in this region  and the observation that Notch can antagonize BMP signaling in other neuronal cell types  suggest that the Notch pathway may regulate this process. Utilizing both loss- and gain-of-function approaches, we demonstrate that an antagonistic interaction between Notch and BMP receptor signaling in cerebellar progenitors regulates their maintenance and differentiation within the rhombic lip throughout embryonic development.
Loss of Notch1 in the cerebellar primordium increases rhombic lip neurogenesis
By E12.5, mutant embryos exhibit a marked decrease in the size of the cerebellar primordium in comparison to wild-type littermates. Nevertheless, no obvious increase in cell death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Additional File 2, or caspase-3 immunohistochemistry), or decrease in proliferation (short term bromodeoxyuridine incorporation) in the residual cerebellar ventricular zone was observed at this stage (data not shown). Following the upregulation of Mash1 in the mutants at E10.5 (Figure 2d, e), Mash1 expression is decreased in all but the most rostral territory of the ventricular zone in comparison to wild type at E12.5 (Figure 2l, m). In contrast, an increase in Math1 expression is still evident in the E12.5 mutants, and scattered Math1+ cells are observed in a broader area of the ventricular zone in comparison with sections from wild type littermates at the same medial-lateral position (brackets in Figure 2n, o). This Math1 expression pattern in the mutant resembles that observed in the most medial sections from wild-type animals, where the cerebellar primordium is thinner and in closer proximity to the midline and roof plate. The increase in subpial distribution of Math1+ cells in the mutant could be accounted for by an increase in migration rate away from the rhombic lip, which is consistent with the observation that Math1 activity is required for subpial migration of rhombic lip neurons [6, 28].
Surprisingly, we also observed that granule cell precursors (GCPs), a rhombic lip derived population specified after the DCN, appear to be generated to some extent in the mutant, although there is a pronounced decrease in caudal regions (Figure 4c, d). The persistence of granule cells in the mutant may reflect the fact that, while the En1cre driver used in these experiments recombines the vast majority of the mes/r1 primordium, the most lateral regions of the cerebellar primordium escape recombination (data not shown). Thus, it is possible that some granule cells are generated laterally and migrate medially to populate the rostral external granule layer (EGL). Alternatively, as discussed in more depth below, there may be distinct lineage-restricted pools of rhombic lip progenitors that are maintained independently of Notch activity until they begin to divide asymmetrically to produce neurons.
The level of Notch activity in cerebellar progenitors regulates their cell fate
To examine the effect of constitutive Notch activation in cerebellar progenitors, we performed injections with a retrovirus expressing the intracellular domain of the Notch receptor (Notch ICD), which is known to result in ligand independent activation of the Notch signaling pathway . Injections of Notch1 ICD expressing retroviruses at E9.5 resulted in infected cells developing primarily into Bergmann radial glia (Figure 5c) as shown by their radial morphology and immunohistochemical co-labeling with brain lipid-binding protein (BLBP; red)  and PLAP (green; Figure 5f inset). These gain-of-function experiments demonstrate that constitutive Notch activity in cerebellar progenitors prevents these cells from developing as rhombic lip derivatives. While several recent reports have described a role for Notch signaling in Math1+ lineages following their specification [35, 36], our results argue that, in those contexts, Notch signaling must be regulated in a dynamic manner such that subsequent phases of differentiation can occur.
Notch1 activity inhibits BMP signaling at the level of Msx1/2 expression
The observation that Notch activity can block the induction of Cath1 by BMP signaling in cerebellar progenitors prompted us to try to determine at what level these pathways intersect within the cell. Electroporations in chick cerebellar primordia of caBMPR alone or caBMPR and Notch1 ICD were stained by immunohistochemistry for phosphorylated Smad1, a direct readout of BMP receptor signaling activity . Smad1 is a transcription factor that, upon phosphorylation by the BMP receptor serine/threonine kinase activity, forms a heterodimer with Smad4 and translocates to the nucleus to activate transcription of target genes (for example, Msx1/2; Figure 6h) . As shown in Figure 6, the levels of phosphorylated Smad1 were elevated in both caBMPR (Figure 6i) and caBMPR/Notch1 ICD (Figure 6k) electroporated tissue, demonstrating that expression of the Notch ICD does not interfere at this stage of the BMP signaling pathway. However, while electroporation of caBMPR into the cerebellar primordium (dashed oval) resulted in ectopic expression of Msx1/2 in the ventricular zone (Figure 6j), this induction was suppressed when Notch1 ICD was co-electroporated (Figure 6l). Counts of GFP+/Msx1/2+ cells in the ventricular zone of caBMPR and caBMPR/Notch1 ICD electroporated cerebella from three embryos each are shown in the graph and indicate that, while approximately 80% of ventricular zone cells transduced with caBMPR express Msx1/2, this percentage drops to around 10% when Notch1 ICD is co-transduced. Thus, expression of the Notch1 ICD antagonizes the BMP signaling pathway at the level of Msx1/2 expression.
We have examined the early stages of cerebellar development to gain an understanding of how neurogenesis in the rhombic lip is regulated throughout embryogenesis. We find that Notch signaling is critical for controlling the timing of induction of rhombic lip neurons from the cerebellar progenitor pool as well as for maintaining a progenitor population for subsequent waves of neurogenesis. Using in vivo gain-of-function methods, we show that the neural differentiation of cerebellar progenitors can be inhibited by constitutive activation of the Notch1 signaling pathway during early embryogenesis, and that cell autonomous downregulation of Notch activity via expression of Delta1 at early embryonic stages (E11.5) increases the responsiveness of cells to differentiate as rhombic lip neurons. Furthermore, we find that activation of the BMP signaling pathway can induce the rhombic lip proneural gene Math1 ectopically in the ventricular zone, and that simultaneous activation of the Notch pathway blocks this inductive effect at the level of Msx expression. Thus, we propose that antagonism between the Notch and BMP signaling pathways regulates the differentiation of cerebellar progenitors throughout the period of neurogenesis in the rhombic lip.
We and others have recently shown that there is an ongoing induction of Math1 in the cerebellar rhombic lip that produces distinct populations of neurons over time; here, we find that this inductive process is regulated by interactions between the Notch and BMP signaling pathways. However, at present little is known about the cerebellar progenitors that give rise to rhombic lip Math1+ lineages, and whether they are composed of a number of lineage-restricted progenitor populations or a single pool of progenitors. Previous work from our lab and others suggests that the neural progenitor cells within the ventricular zone are heterogeneous [43–45], and that while at early embryonic stages some progenitor lineages are being maintained by symmetric non-neurogenic divisions, others are becoming neurogenic and divide asymmetrically to produce differentiating neurons. It appears likely that Notch signaling is particularly critical in maintaining a progenitor lineage during asymmetric cell divisions. In this context, our fate mapping results shown in Figure 4 may indicate that there are multiple Math1-negative progenitor lineages within the cerebellar progenitor population that give rise to rhombic lip neurons. While the total number of hindbrain neurons (PBG, MPT, LPB) specified appears to be relatively unaffected by loss of Notch1, the LPB neurons appear to be increased in number at the expense of the MPT neurons and DCN, suggesting that these rhombic lip derived neurons may arise from a common progenitor lineage. The persistence of GCPs in this experiment may reflect that there is a distinct progenitor population for GCPs that is maintained independently of Notch activity during the production of hindbrain and DCN until specification of GCPs begins. This possibility could account for the observation that only the early born (rostral) GCPs appear to be specified in the conditional Notch1 mutant, in that Notch signaling would be required to maintain the GCP progenitor pool during the period of GCP induction, and thus these progenitors would be rapidly depleted in the absence of Notch activity. Alternatively, the GCPs that are observed may have arisen from the most lateral regions of the cerebellar primordium that are not recombined by the En1-Cre driver since these cells (but not DCN) are known to migrate from lateral to medial positions .
The role of BMP signaling in neural induction has been studied in many contexts, as has the anti-neurogenic role of Notch signaling. However, little is known at present about how these two pathways interact in vivo to regulate neurogenesis. A recent study on cell fate determination in neural crest derivatives demonstrated a dominant effect of Notch activation in preventing neuronal differentiation in response to BMP signaling in vitro . In this study, it was found that transient Notch activation in neural crest progenitors resulted in a permanent gliogenic fate switch. In the context of the cerebellum, both Notch and BMP signaling have been shown to regulate neurogenesis, but it is not clear that these signaling pathways interact in the same manner as observed in the neural crest. We find it unlikely that cerebellar progenitors that are maintained in the ventricular zone via Notch signaling are committed exclusively to a glial fate. Rather, at this stage of progenitor maturation, Notch signaling acts to inhibit responsiveness to BMP signaling but is not itself instructive until later developmental stages.
Our data demonstrating that the Notch and BMP receptor signaling pathways interact competitively within cerebellar progenitors suggest that the Notch1 ICD and activated Smad1/Smad4 moieties converge on a common target. It has been reported that the Notch1 ICD binds to the core transcriptional activator p300 , and forms a complex with p300/CBP-associated protein (P/CAF), Rbp-J and Mastermind like-1 (MAML1) to activate transcription . Recently, it has been shown that phosphorylated Smad1 can be co-immunoprecipitated with the Notch-1 ICD in the presence of p300 and P/CAF , suggesting that these core transcription co-activators may mediate the interactions between Notch and BMP signaling. An intriguing complement to the above is suggested by a recent report that Smad1 contains inhibitory phosphorylation sites that are targeted by the mitogen-activated protein kinase (MAPK) signaling cascade [50, 51]. Fibroblast growth factor (FGF) signaling from the isthmus could, therefore, potentiate Notch signaling in the cerebellar primordium by decreasing the responsiveness of rostral cerebellar progenitors to BMPs secreted from the roof plate.
The cerebellar rhombic lip is a unique germinal zone that produces specific hindbrain nuclei, DCN, and granule cell precursors in a temporally regulated manner. Our results provide a mechanistic explanation for how the ongoing induction of Math1 in cerebellar progenitors is regulated in the rhombic lip throughout embryogenesis. Because the initiation of neurogenesis in the rhombic lip begins immediately following neural tube closure, and continues late into embryonic development, we find a critical role for Notch1 signaling in the cerebellar primordium during this period to inhibit cerebellar progenitors from responding prematurely to rhombic lip inductive signals. We suggest this represents the first of a set of distinct roles that Notch1 performs in the embryonic cerebellum. We propose Notch1 signaling acts iteratively in the cerebellar progenitor population, first by inhibiting the overproduction of early rhombic lip derived neurons, then by regulating neurogenesis in the ventricular zone , and finally by stimulating gliogenesis [20, 33]. Furthermore, in addition to Notch1, other Notch family members have been shown to regulate granule cell precursor development during embryogenesis through possible reciprocal interactions with Math1 . Postnatally, Notch2 signaling has been shown to regulate the maturation of granule cell precursors in the EGL by maintaining them in a proliferative state . Thus, it appears that the Notch signaling pathway acts to arrest the differentiation state of cerebellar precursors at multiple developmental stages. Deciphering how the Notch signaling pathway modulates the responsiveness of neural progenitors to developmental cues will be crucial for understanding the regulation of growth and differentiation of the central nervous system throughout embryogenesis.
Mouse genotyping and tissue preparation
Engrailed1-cre, floxed Notch1, Math1-LacZ, and Rosa26 stopLacZ mice were genotyped as previously described [25–27, 29]. To generate En1cre; floxNotch1 embryos, the En1-cre line was crossed with homozygous floxNotch1 animals, and the resultant En1-cre; floxNotch1/+ males crossed with homozygous floxNotch1 females. En1cre; floxNotch1; Math1-LacZ animals were generated by crossing En1cre; floxNotch1 (c/+) with Math1-LacZ; floxNotch1 (c/+). The morning of the observed plug was considered day 0.5. Embryos collected at E10.5 to E14.5 were fixed in ice cold 4% paraformaldehyde/phosphate-buffered saline (PBS) for 1 to 2 hours, washed in PBS, and equilibrated in 30% sucrose/PBS overnight. Older embryos and adults were perfused transcardially and the brains dissected prior to sucrose equilibration. For cryosectioning, embryos were mounted in Tissue-Tek OCT (VWR, West Chester, PA) and sectioned at 14 to 20 μM.
In situ hybridization and immunohistochemistry
Section antisense RNA in situ hybridization was performed as previously described , with the following probes: Notch1, Math1, Mash1, Msx2, and Cath1. Immunohistochemistry with antibodies against Math1 (rabbit-antiserum; kind gift of J Johnson (UT Southwestern Medical Center), calbindin (rabbit antiserum; Swant, Bellinzona, Switzerland), human placental alkaline phosphatase (sheep α-PLAP antiserum; American Research Products, Belmont, MA, USA), Zic2 (rabbit antiserum; kind gift of J Aruga (RIKEN Brain Science Institute), BLBP (rabbit antiserum, kind gift of T Anthony and N Heintz (Rockefeller University), phosphorylated Smad1 (purified rabbit IgG; Cell Signaling Technologies, Danvers, MA, USA), and Msx1/2 (mouse monoclonal antibody 4G1, ascites, Developmental Studies Hybridoma Bank, Iowa City, IA, USA) was performed as previously described .
Preparation, injection, and histochemical analysis of control (CLE) and Notch1 ICD (CLEN) retroviruses have been described previously . Full-length cDNA for human Delta1 was subcloned into pCLE downstream of the EF1α promoter (CLED) and virus prepared as above. We analyzed six to eight P21 brains each for the CLED and CLEN experiments and found three to four for each that had substantial infections in the cerebellum.
In ovo electroporation was performed as described previously , with the following modifications. Specifically, cDNA for the Notch1 ICD was subcloned into the chick expression vector pMiwIII, such that its expression was directed by the chicken β-actin promoter. The constitutively active BMP receptor 1b and GFP constructs have been described previously . Plasmids were injected into the ventricle at the mid-hindbrain boundary (GFP, 0.2 μg/μl; Notch1 ICD, 1 μg/μl; and caBMPR, 0.33 μg/μl) and two electrodes placed on either side of the neural tube. Five rectangular electric pulses of 15 volts (50 ms each) were then delivered. Embryos were recovered after approximately two days further incubation, fixed for 1 hour in ice cold 4% paraformaldehyde/PBS, washed in PBS, and allowed to equilibrate overnight in 30% sucrose/PBS prior to mounting and cryosectioning. At least three electroporated embryos were analyzed for each experiment.
We would like to thank Nick Gaiano for pioneering this study, Staci Rakowiecki and Yuan Yuan Huang for technical assistance, James Li for valuable assistance with in ovo electroporations, and the members of the Fishell lab and Alex Schier for critical reading of the manuscript. We thank J Johnson for the Math1 antibody, and the Math1 and Cath1 probes, J Rossant for the Notch1 probe, F Guillemot for the Mash1 probe, S Artavanis-Tsakonas for the full length Delta1 cDNA, J Timmer and L Niswander for the GFP and caBMPR1b chick electroporation constructs, T Anthony and N Heintz for the anti-BLBP antibody, and J Aruga for the anti-Zic2 antibody. This work was supported by an NIH postdoctoral fellowship (1F32NS42525-03) to RPM, and a NIH grant (R01 NS032993) to GJF.
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