Expression of S100B during embryonic development of the mouse cerebellum
© Hachem et al; licensee BioMed Central Ltd. 2007
Received: 28 August 2006
Accepted: 15 March 2007
Published: 15 March 2007
In the cerebellum of newborn S100B-EGFP mice, we had previously noted the presence of a large population of S100B-expressing cells, which we assumed to be immature Bergmann glial cells. In the present study, we have drawn on this observation to establish the precise spatio-temporal pattern of S100B gene expression in the embryonic cerebellum.
From E12.5 until E17.5, S100B was expressed in the primary radial glial scaffold involved in Purkinje progenitor exit from the ventricular zone and in the Sox9+ glial progenitors derived from it. During the same period coinciding with the primary phase of granule neuron precursor genesis, transient EGFP expression tagged the Pax6+ forerunners of granule precursors born in the cerebellar rhombic lip.
This study provides the first characterization of S100B-expressing cell types of the embryonic mouse cerebellum in a high-resolution map. The transient activation of the S100B gene distinguishes granule neuron precursors from all other types of precursors so far identified in the rhombic lip, whereas its activation in radial glial precursors is a feature of Bergmann cell gliogenesis.
The medial and lateral compartments of the alar plate of the metencephalon have been shown to confer distinct patterning information during neurogenesis and gliogenesis of the embryonic cerebellum (Cb) (for a review see ). Whereas cerebellar inhibitory neurons like Purkinje cells (PCs) and Bergmann glial cells are generated in the medial portion of the fourth ventricle (V4) , primary precursors of granule neurons (GPs) are produced from its lateral recesses, the so-called cerebellar rhombic lip (RL) . During the third week of gestation in the mouse, radial glial cells of the medial aspect of the ventricular zone (VZ) progressively retract their somata towards the cortex and actively divide to generate precursors of Bergmann glial cells and astrocytes . At the same time, young PCs migrate radially from the neuroepithelium to the surface in a strictly caudal-to-rostral order, paralleling the emergence of cohorts of neuron precursors from the RL and their superficial migration along the dorsal surface of the Cb primordium .
Using a line of transgenic mice in which tamoxifen-inducible Cre expression at the time of birth results in permanent β-galactosidase labeling, RL precursors destined to populate the internal granule layer (IGL) were estimated to be generated in a rostral-to-caudal sequence between E13 and E17 . At the time, these Lac-Z-labelled IGL cells were thought to represent a homogenous population of granule neurons. A recent study has provided evidence that besides granule cells, the cerebellar RL gives birth to another IGL population of neurons, unipolar brush cells (UBCs), between E14.5 and E19.5 . Furthermore, granule and UBC neurons are preceded by glutamatergic Deep Cerebellar Nuclei (DCN) neurons. The first DCN neuron precursors are born in the RL at around E10. At E11.5, they stream over the entire dorsal surface of the Cb, and from E12.5 until E14.5 they aggregate in the NTZ, a transient zone of differentiation [6, 8, 9].
The RL therefore appears to be highly dynamic, giving rise to distinct neuronal populations, and a consensus has now emerged from all these fate-mapping studies, which redefines the RL as a functional rather than anatomical entity. The RL is now considered as a territory within rhombomere 1 which is required for the sequential generation of all cerebellar and extracerebellar superficial migratory streams, therefore contributing neurons to the proprioceptive/vestibular/auditory sensory network which task is to sense the organism's position in space . The cells of this functional system all depend on the expression of the basic-helix-loop-helix transcription factor Math1for their genesis , and the paired and homeodomain containing transcription factor Pax6 for their proper migration .
In S100B-EGFP mice, we had previously noted that the transgene is activated during histogenesis of the Cb between E13.5 and P3, and reported the existence of a large population of S100B+ cells in the Cb cortex of newborn mice . Because S100B is commonly used as a marker of Bergmann glia and white matter astrocytes in the Cb of adult mice , we assumed that its presence in the embryonic Cb marked their precursors. S100B is a small EF-hand calcium and zinc binding protein, highly expressed in the adult vertebrate central nervous system (CNS) along with five other S100 family members . The S100B protein sequence is extremely well conserved (> 97%) among mammals, suggesting that it is endowed with important physiological functions . However, as judged by the vitality of mice strains lacking the S100B protein, there must be a fundamental resiliency of the developmental program involving the S100B protein [15, 16].
S100B is a highly soluble protein implicated in the initiation and maintenance of a pathological, glial-mediated pro-inflammatory state, and its presence in biological fluids is a well-established biomarker for severity of neurological injury and prognosis for recovery . A consensus sequence for S100B target proteins was published as (K/R)(L/I)xWxxIL and matches a region in the actin capping protein CapZ . Several additional S100B targets are known, including p53, two NDR kinases , the RAGE receptor , protein kinase C, and Gap-43 [22, 23]. The range of effector proteins so far identified suggests roles in the regulation of transcription, cell-cycle progression , and cell morphology. In astrocytes where S100B is abundantly expressed, its best-characterized roles involve modulating protein-protein interactions of all three classes of cytoskeletal structures, and preventing these interactions blocks astrocyte stellation .
With the present study, we sought to determine the precise spatio-temporal pattern of S100B expression in the embryonic Cb using the S100B-EGFP mouse as a model. We found that S100B protein expression in radial glial cells of the medial portion of the cerebellar VZ marks the onset of gliogenesis. In addition, we provide evidence for transcriptional activation of the endogenous S100B gene being associated with the prenatal phase of GP production in the RL.
S100B expression in the cerebellum (E17.5)
Between E13.5 and E17.5, migratory Purkinje progenitors are subject to "contact guidance", a process by which they adhere to radial glial processes to reach their final destination in the cortex . From E14.5 until P7, Bergmann glial cells are thought to derive from primary radial glial cells that translocate their somata from the VZ into the Purkinje cell layer, giving rise to a secondary radial glial scaffold . Detection of S100B in the cerebellar radial glial scaffold at E17.5 therefore incited us to go back in time and determine exactly when, and in which cell type, transcription of the S100B gene is activated in the embryonic Cb.
S100B expression in the cerebellar radial glial scaffold (E14.5–E16.5)
Together these results indicated that before midline fusion of the Cb plates, EGFP and S100B were co expressed in the Sox9+ BLBP+ primary radial glial scaffold traversing the Cb primordium from the IC posterior limit to the RL, with a higher level of expression near the midline. In addition, EGFP;S100B co-expression was prominent in a median stretch of inferior tectal neuroepithelium directly abutting the rostral Cb primordium.
Characterization of the S100B-EGFP cell population of the CTZ (E13.5–E16.5)
Based on the evenly distribution and morphology of EGFP+ cells connected to the pial surface via their apical radial process (Fig. 4E,F), which characterize prospective Bergmann glial cells , we conclude that the radial glia-derived EGFP+ population present in the Cb primordium between E13.4 and E17.5 likely contains glial precursors some of which are already contributing to the secondary Bergmann radial glial scaffold that will later be used by GPs to migrate from the EGL to the IGL.
Characterization of the S100B-EGFP cell population of the RL (E12.5–E15.5)
The non DCN nature of EGFP+ RL precursors was tested by performing immunohistochemistry with a pair of antibodies directed against the transcription factor Pax6 expressed in the RL throughout its neurogenetic interval , and the transcription factor Olig2 known to label the NTZ starting on E12.5 . The high proportion of EGFP+ Pax6+ double positives present in the lateral portion of the RL at E12.5 is illustrated in figures 6B and 6C (colored dots). Their non-DCN nature was inferred from the discontinuity that existed at E13.5, between the NTZ already filled with Olig2+ nuclei and the territory of EGFP expression restricted to the RL and posterior EGL (Fig 6D).
From our results and the results provided by a recent study that will be discussed below , we believe that transient expression of the S100B-EGFP transgene is a specific marker of the primary phase of GP genesis in the embryonic RL.
Discussions and conclusions
The aim of the present study was to establish the spatio-temporal pattern of S100B expression in the mouse embryonic Cb. We compared the distribution of the S100B-EGFP reporter to that of the endogenous S100B protein from E12.5 to E17.5. Our results establish the S100B protein as a marker of the BLBP+ Sox9+ primary radial glial scaffold starting on E13.5. In addition, and although the S100B protein was not detected, we provide evidence that S100B-EGFP expression in Pax6+ derivatives of the RL marked the onset of primary GP production. In addition, our results suggest that depending on the site of S100B synthesis, primary radial glial scaffold and derivatives or RL and neuron precursors, S100B may be retained within the cell or secreted.
The onset of S100B expression in the cerebellar ventricular zone: marking the transition from neurogenesis to gliogenesis in primary radial glial cells
Although we found no mention of the S100B protein being expressed in the mouse embryonic cerebellar radial glia, the S100B mRNA was detected in the rat cerebellar radial glia . Additionally, in a study designed to analyze the expression pattern of 158 murine orthologs of genes identified on human chromosome 21, the S100B mRNA was detected in the VZ of the mouse embryonic Cb on whole mounts and tissue sections .
The radial glial origin of EGFP+ S100B+ cells present in the CTZ in increasing number from E14 to E17.5 is also consistent with several reports showing that in addition to being essential for PC exit from the VZ between E13.5 and E17.5 , the primary radial glia is linked to gliogenesis from E14 to P7 . According to 3H thymidine and BrdU birth dating studies, PCs are produced between E11 and E13 , and expression of calbindin-1 is first detectable at around E14 in post mitotic PCs that have migrated a short distance away from the VZ .
Here we show that EGFP+ cells that detach from the VZ and migrate into the CTZ beginning on E14.5, are not post-mitotic Purkinje cells. While migrating towards the surface most EGFP+ cells lose their connection to the VZ but not their connection to the pial membrane, a feature of prospective Bergmann glial cells. Finally, we show that near the onset of gliogenesis (E16.5), Sox9 expression is maintained in some radial glia-derived EGFP+ cells. This is in line with a previous report showing that most, if not all glial precursors in the Cb take the form of radial glial cells  and Bergmann glial cells maintain Sox9 expression from the early migrating progenitor stage through adulthood .
Several molecules known to be expressed in Bergmann glial cells of the adult mouse Cb start being expressed in the embryonic radial glia, at around E14. They include the intermediate filament protein vimentin , the lipid binding protein BLBP , the enzyme Glutamine synthetase , the extra cellular matrix molecule with neuron-glia cell adhesion activity Tenascin-C , the glutamate transporter Glast , the enzyme 3PGDH involved in L-serine biosynthesis , the Punc neural cell-adhesion molecule , and the transcription factor Sox9 . We now suggest that S100B be added to the list.
The midbrain-hindbrain junction: a privileged site of S100B expression before cerebellar midline fusion
The strongly S100B+ median stretch of ventral neuroepithelium we observed at the midbrain-hindbrain junction (Fig 3E) is reminiscent of a previously reported vimentin+ radial glial structure linking the IC to the Cb in E20 rat embryos . In the mouse, this isthmic territory is thought to provide a cellular substratum and the signals essential for fusion of the cerebellar plates along the dorsal midline . In addition, this territory is subsequently relinquished to the velum medullaris, a neuron-free sheet of cells that is very short before birth but which develops during the following days and links the anterior pole of the vermis to the inferior colliculus.
S100B: a rhombic lip marker of primary granule precursor genesis
The RL is a specialized germinative epithelium that arises as a result of the ongoing interaction between the neural tube and the non-neural roof plate ectoderm of V4 (reviewed in ). Its main derivatives include primary precursors of glutamate releasing excitatory granule neurons, by far the most numerous neurons in the CNS, which relay afferent, excitatory information from mossy fibers to Purkinje neurons. In addition, the RL produces precursors of DCN neurons, the main output centers of the Cb , and cortical UBCs, which amplify inputs from vestibular ganglia and nuclei .
In the present study, we provide evidence for transcription of the S100B gene being specifically activated in the RL during the primary phase (E13–E17) of GP genesis. First, we have shown that expression of the S100B-EGFP transgene is initiated in Pax6+ precursors present in the RL at E12.5, which is after the bulk of DCN neuron precursors have left the RL  and reached the NTZ . The non-DCN nature of the RL Pax6+ precursors is substantiated by the existence of a clear boundary, at E13.5, between the EGFP-tagged RL and the EGFP-negative NTZ (Fig 5D). Such a discontinuity is not expected to occur when using a LacZ reporter gene driven by the Math1 locus .
Second, we think we can exclude UBC precursors as possible candidates for S100B-EGFP expression on the basis of their mode of migration that is different from the subpial mode of Pax6+ EGFP+ precursor migration within the EGL. Both populations of GPs and UBC precursors are known to share expression of the RL markers Pax6 and Math1. However, unlike UBC precursors which stream from the RL and posterior EGL into the developing white matter, and are therefore excluded from the anterior EGL , EGFP+ Pax6+ precursors invested the entire EGL with their leading process contacting the pial surface (Fig. 5A,C), a signature of migrating GPs [44, 46]. Hence, we believe that transient expression of the S100B gene is a specific marker of the primary phase of GP genesis in the embryonic RL.
Finally, although we could not detect the S100B protein in the mouse RL, evidence exists for the presence of the S100B protein in the hamster EGL , and S100B mRNA in the murine cerebellar VZ including the RL [12, 34]. Therefore, one interpretation for our results is that both the endogenous S100B gene and the transgene are expressed in the RL but the S100B protein cannot be detected because its cytoplasmic level is below detection limit, or because it is released in the intercellular space. The latter cannot be expected from the reporter EGFP protein since it is not a fusion of S100B and EGFP .
How is the S100B gene activated during cerebellar morphogenesis?
Before cerebellar midline fusion, the medial-most portion of the Cb neuroepithelium and abutting inferior tectal neuroepithelium, both co expressing EGFP and S100B at the highest level (Fig. 2), are also known territories of high En-1 expression . This designates En-1 as a potential inducer of S100B gene expression in the Cb. Beginning on E8.5 in the mouse, the Fgf-8 molecule produced in the isthmic orgnizer  induces expression of a series of genes including Wnt-1 and En-1 . Wnt-1 maintains En-1 expression, which in turn, positively regulates Fgf-8, resulting in amplification of the Fgf-8 signal necessary for proper Cb specification and development [49, 50].
Interestingly, the earliest site of strong S100Bexpression in S100B-EGFP mice is the notochord beginning on E10.5 (Hachem and Legraverend, unpublished), and inhibition of En-1 expression by antisense targeting of early somite mouse embryos resulted in the loss of S100B expression in the notochord region subjacent to affected neural tube segments . Therefore, S100B may be a downstream component of the Wnt/En-1 regulatory cascade involved in the specification of both the notochord and Cb.
Which function(s) for S100B during cerebellar morphogenesis?
In the mouse embryonic Cb, radial glial cells and immature astrocytes express the intermediate filament vimentin , a protein with which S100B was shown to interact in vitro . S100B also binds to and activates in a Ca2+-dependent manner NDR-1 and NDR-2, two nuclear proteins that belong to an evolutionary conserved subfamily of serine/threonine protein kinases involved in the regulation of cell morphology . These types of interaction are consistent with S100B participating in vivo in the establishment and maintenance of a radial glial phenotype in the medial portion of the Cb where S100B is intracytoplasmic.
S100B may also be released from cerebellar rhombic lip EGFP+ Pax6+ precursors and promote the extension and branching of their neurites as illustrated in Fig. 6C. In 1985, Kligman and Marshak identified the extra cellular disulfide form of S100B as the molecule responsible for neurite extension of cultured chicken embryonic cortical neurons and named it "Neurite Extension Factor" . This NEF effect of S100B was later demonstrated on various types of neurons including cortical neurons , serotonergic mesencephalic neurons , dorsal root ganglion neurons  and spinal cord neurons , but the mechanism responsible for the NEF effect is unknown.
Another possible role exerted by the S100B protein released in the extracellular space is that of a trophic factor. Added in ovo at physiological concentrations, S100B was indeed capable of preventing the naturally occurring death of chicken motor neurons . The neurotrophic activity of S100B is thought to involve activation of NF-kappaB , binding to the receptor for advanced glycation end products (RAGE) and increased expression of the anti-apoptotic protein Bcl-2 .
Transgenic S100B-EGFP mice , and S100B knockout mice  were housed under standard laboratory conditions in a 12-h light/dark cycle with access to food and water ad libitum. Experiments were performed according to the principles of laboratory animal care, following the guidelines approved by INSERM. Adult mice were allowed to mate overnight, and females were inspected for the presence of vaginal plugs the next morning (E0.5). Pregnant females were anesthetized with sodium pentobarbital and perfused through the ascending aorta with phosphate-buffered saline (PBS, pH 7.4) followed by 300 ml of fixative composed of 4% Para formaldehyde in 0.1 M phosphate buffer, pH 7.4. Embryos were quickly removed from the uteruses, anesthetized by hypothermia, and sacrificed by decapitation.
Embryos were cryoprotected by immersion in 30% sucrose in PBS for 12–24 h at 4°C, embedded in OCT compound (Tissue-Tek, Washington, DC) and frozen at -30°C. Tissue sections (15 μM) were obtained in a JUNG CM 300 cryostat (Leica), mounted onto poly-lysine-coated slides, and stored at -20°C. After several rinses in PBS, frozen sections were incubated in PBS containing 0.1% Triton X-100 and 10% goat serum for 1 h at room temperature (RT) and then incubated for 24 h at 4°C with primary antibodies followed by incubation with secondary antibodies for 1 h at RT. Primary antibodies were diluted in PBS containing 0.1% Triton X-100 and secondary antibodies were diluted in PBS containing 0.05% bovine serum albumin (BSA). After three rinses in PBS, sections were mounted in Mowiol (Calbiochem, La Jolla, CA) containing 2.5% 1,4-diazabicyclo- (2.2.2) octane (DABCO). The specificity of S100B immunolabeling was confirmed on sections of S100B null embryos (data not shown).
Primary and secondary antibodies
The following antibodies were used: rabbit polyclonal antibodies specific for S100B (1:1,000; Dako, Glostrup, Denmark, or Carpinteria, CA); Olig2 (1:6,000; obtained from Dr. Takebayashi, National Institute for Physiological Sciences, Okazaki, Japan); Pax6 (1:500; Berkeley Antibody Company, Richmond CA); Sox9 (1:500; Santa Cruz Biotechnology, Santa Cruz, CA); calbindin-1 (1:1000; Swant, Bellinzona, Switzerland). We used secondary donkey anti-rabbit IgG Cy3-F (ab0) 2 conjugates (1:1,000; Jackson ImmunoResearch, West Grove, PA). The specificity of S100B immunolabeling was confirmed on brain sections of S100B knockout embryos.
Confocal microscopy and illustrations
A Bio-Rad 1024 confocal laser scanning microscopic (CLSM) system equipped with an argon/krypton mixed gas laser was used for the analysis of adult and embryonic S100B-EGFP mice. Non-stacked CLSM images were obtained, representing optical sections with a depth of field of 0.5–3 μM. Two laser lines emitting at 488 nm and 568 nm were used for exciting EGFP and CY3-conjugated secondary antibodies, respectively. Four inputs were averaged to reduce the background noise, and green and red images were collected sequentially. Data acquisition and processing were controlled by the Laser sharp 1024 software and processing system. Unless otherwise stated, we marked EGFP+ Pax6- cells with asterisks and EGFP+ Pax6+ double positives with colored dots (green over red pax6+ nuclei, red over green EGFP+ cells). Pax6+ EGFP- cells were left unmarked. A cell was considered EGFP+ when both nucleus and cytoplasm were stained, or if a rim of green cytoplasm could be clearly assigned to a given nucleus. As a result, the number of double positives was most probably under evaluated. The pial and ventricular surfaces were outlined with white dashed lines; the limit between neuroepithelium and choroid plexus epithelium was marked with a blue dashed line; the choroid plexus epithelium of the fourth ventricle was outlined with a red dashed line.
- V :
- VII :
- ant :
- aq :
- BLBP :
brain lipid binding protein
- cap :
- Cb :
- CNS :
central nervous system
- CP :
chroroid plexus of the fourth ventricle
- Cpe :
choroid plexus epithelium
- CTZ :
cortical transitory zone
- DCN :
deep cerebellar nuclei
- di :
- dors :
- EGFP :
enhanced green fluorescent protein
- egl :
external granule layer
- En-1 :
- Fgf-8 :
fibroblast growth factor 8
- Gap43 :
growth-associated protein 43
- GFAP :
glial fibrillary acidic protein
- GP :
cerebellar granule neuron precursor
- IC :
- lat :
- med :
- mes :
- NDR :
nuclear (Saccharomyces cerevisiae) Dbf2-related kinase
- NTZ :
nuclear transitory zone
- PC :
- Post :
- RL :
cerebellar rhombic lip
- scc :
semi-circular canal of otic vesicle
- tel :
- UBC :
unipolar brush cells
- V4 :
- VZ :
- Wnt-1 :
We thank Dr A. Marks, from the Banting and Best Department of Medical Research, University of Toronto, Canada, for the gift of the S100B KO mouse. We thank N. Lautredou for her assistance in the acquisition of confocal images, and A. Delalbre for maintaining the S100B-EGFP and S100B KO transgenic lines. We thank Drs. P. Jay, H. Takebayashi, and F. Ango, for the gifts of antibodies against Sox9, Olig2, and calbindin, respectively. We are grateful to Dr. D. Joubert and J. -C. Deloulme for helpful discussions and for critical reading of the manuscript. Sabira Hachem received a scholarship from the Ministère de la Recherche et de la Technologie.
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