FMRP regulates postnatal neuronal migration via MAP1B

  1. Salima Messaoudi
  2. Ada Allam
  3. Julie Stoufflet
  4. Theo Paillard
  5. Anaïs Le Ven
  6. Coralie Fouquet
  7. Mohamed Doulazmi
  8. Alain Trembleau
  9. Isabelle Caille

  • Curated by eLife

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    This study addresses the role of FMRP in the migration of newborn neuroblasts in the postnatal brain. Through extensive and convincing analysis of living imaging videos, the authors showed that neurons with FMRP deletion migrate aberrantly and exhibit defects in nucleokinesis and centrokinesis. The study presents a valuable finding on the mechanism of neuroblast migration in the postnatal brain.

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Abstract

The fragile X syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of autism spectrum disorder. FXS results from the absence of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal rostral migratory stream (RMS) neurons in Fmr1 -null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary Fmrp mRNA target implicated in these migratory defects is microtubule-associated protein 1B (MAP1B). Knocking down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.

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  1. Version published to 10.7554/elife.88782.3 on eLife
  2. Version published to 10.7554/elife.88782 on eLife
  3. Version published to 10.7554/elife.88782.2 on eLife
  4. eLife

    Author Response

    The following is the authors’ response to the original reviews.

    To Reviewer #1

    We sincerely appreciate the constructive and insightful comments provided by the reviewer. Their valuable suggestions have been meticulously considered, leading to comprehensive modifications within the article.

    In addition, we want to stress that we have implemented a significant additional modification by introducing a new figure (Fig. 6). This figure highlights the collaborative impact of FMRP and Map1B on the microtubular structure of migrating neurons. We firmly believe that this molecular elucidation of the migration phenotype constitutes a noteworthy addition to our work.

    Public Review

    (1) We have taken the necessary steps to enhance the material and methods section of our neuronal migration analysis. We apologize for any initial lack of detail, including the omission of information on sinuosity index and directionality radar. Regarding the query about speed, we want to clarify that it indeed encompasses the percentage of pausing time. The speed is calculated by dividing the total distance traveled by the cell by the total time it migrated.

    (2) We would like to provide a clarification regarding the statistical analysis in our figures. The figures now represent the median, and the legend indicates the median along with the interquartile range. This approach is in line with the use of non-parametric analysis for variables that do not adhere to a normal distribution. Regrettably, in the previous version, there was an oversight in the figure legends where the mean, along with the standard error of the mean, was incorrectly stated instead of the intended representation of the median. We sincerely apologize for any confusion this may have caused. Moving forward, the corrected legend now accurately reflects the statistical measures used in the analysis.

    The global Kruskal Wallis analysis, followed by Dunn’s post hoc analysis, does indeed indicate that Fmr1 KD globally replicates the Fmr1-null phenotype. However, we concur with the reviewer's point regarding directionality, and we apologize for any lack of precision in the initial version. Upon further analysis, we have identified a significant difference in directionality (Fisher test p < 0.001). This more pronounced directionality defect in the KD could potentially be indicative of a lack of compensation, a factor that may not be at play in the Fmr1 null context. We appreciate the opportunity to address this issue and our revised version includes the necessary details to accurately convey these findings.

    (3) We appreciate the referee's agreement with our perspective.

    (4) In response to the recommendations from all referees, we have expanded both the introduction and discussion sections of our manuscript. The initial brevity of these sections was due to the short format we had initially chosen. We believe that these expansions contribute to a more comprehensive and nuanced presentation of our work, addressing the concerns raised by the referees.

    Recommendations for the authors

    The time stamp and scale bars were added.

    The median versus mean issue is addressed above.

    Figure numbering has been corrected (sorry for the mistake). The efficiency of CK is defined in the Mat and Met section.

    To Reviewer #2

    Public review

    We express our gratitude to the referee for their positive appreciation of our work. We have carefully considered their suggestions and have modified the article accordingly.

    In addition, as said to Referee #1, we want to stress that we have implemented a significant additional modification by introducing a new figure (Fig. 6). This figure highlights the collaborative impact of FMRP and Map1B on the microtubular structure of migrating neurons. We firmly believe that this molecular elucidation of the migration phenotype constitutes a noteworthy addition to our work.

    Recommendations for the authors

    (1) In light of the referee's recommendation, we conducted more resolutive staining of FMRP in SVZ neurons cultured in Matrigel, providing a more precise depiction of its subcellular localization (see Figure 1). Additionally, we have removed the sentence referring to growth cone staining, as it was not visibly present in cultured neurons. We appreciate the guidance from the referee in refining our study.

    (2) We have also added a new figure 4 with better staining of MAP1B in the RMS as well as a more resolutive MAP1B staining in cultured neurons.

    With all due respect, we maintain that the western blot experiments, conducted in three independent experiments, unequivocally support the conclusion of a 1.6X increase in MAP1B in the RMS of Fmr1null mutants, a trend observed in other systems.

    In accordance with the referee's suggestion, we endeavored to quantify RMS immunostainings. Regrettably, the results proved inconclusive. This outcome is not entirely unexpected, as immunostainings are recognized for their inherent challenges in quantification. The additional complexity introduced by neonate perfusion further contributes to the notable interindividual variability observed.

    (3) The efficiency of the two interfering RNAs is now documented in the text. Regarding the directionality radar, as highlighted for Ref 1 (public review, point #2), we acknowledge that, while Fmr1KD generally recapitulates the migratory phenotype of the Fmr1 mutants, more precise statistical analysis reveals differences in directionality, which is now documented. We apologize for the previous lack of precision.

    (4) The suggested experiment of overexpression is interesting but we faced challenges in its execution. Attempts to overexpress MAP1B through intraventricular electroporation of a CMV-MAP1B plasmid resulted in the immobilization of transfected cells in the SVZ, hindering further analysis of migration. We hypothesize that this outcome may be attributed to a discrepancy in the actual dosage of MAP1B in the mutants.

    (5) Concerning this point, and as mentioned above, we have incorporated a crucial piece of information into the manuscript, presented in Figure 6. The data reveal a severe disruption in the microtubular cage surrounding the nucleus of migrating neurons in Fmr1 mutants, a phenomenon rescued by MAP1B knock-down. Based on these findings, we believe we can confidently conclude that the microtubule-dependent functions of MAP1B play a role in the migratory phenotype of Fmr1 mutants. We consider this experiment to be a highly valuable addition to our work, shedding light on the underlying molecular mechanisms.

    To Reviewer #3

    We thank the referee for their insightful comments and have taken their consideration with great considerations.

    In addition and as said above, we want to stress that we have implemented a significant additional modification by introducing a new figure (Fig. 6). This figure highlights the collaborative impact of FMRP and Map1B on the microtubular structure of migrating neurons. We firmly believe that this molecular elucidation of the migration phenotype constitutes a noteworthy addition to our work.

    Public review

    With regard to the perceived 'incompleteness' of our work, we believe that the addition of Figure 6, illustrating the molecular underpinnings of the Fmr1 mutation on the microtubular cytoskeleton and its rescue in the MAP1B KD, significantly enhances the completeness of our study.

    In response to the comment on the introduction and discussion sections, we acknowledge that their brevity was due to the Short Format initially chosen. We have since expanded these sections, incorporating additional information about FMRP and MAP1B and their influences on migration.

    Regarding the La Fata article, as highlighted in our discussion, it's important to note that while the study did not strongly indicate an impact on radial locomotion per se, drawing conclusive results is challenging due to the relatively low number of analyzed neurons. Consequently, we do not believe that it poses a challenge to our findings.

    With respect to MAP1B overexpression, as previously mentioned in response to Ref #2, point 4, our attempts resulted in the inhibition of migration, potentially due to an overdosage of the protein.

    In terms of anatomical consequences, as highlighted in our discussion, while our neurons experience a delay in migration, they eventually reach their destination. Although a delay in migration may not directly result in significant anatomical anomalies, we acknowledge that the timing of differentiation can be crucial. As noted by Bocchi et al. (2017), a delay in the timing of differentiation for neurons reaching their target could lead to notable functional consequences. In any case, we have tOned down any references to the implication for the pathology.

    Recommendation for the authors

    • The size of the figures has been modified

    • The pausing time and sinuosity are now defined

    • The centrin-RFP labeling was indeed too weak in the previous version, which we corrected. We apologize for this.

    • Fig S3 has been revised to address concerns. Notably, the decision to present the two bands for Vinculin and MAP1B separately is intentional. The blot is cut to allow independent development due to the substantial difference in their development times. We believe this approach provides a more accurate representation of the data.

    • The numbering of the figures has been corrected. Sorry for the initial mistake.

    • The Mat and Meth section has been corrected. Please note that we did not use any culture insert in this study.

    • The tittle has been modified

    • Comments about the Map1B overexpression experiment are expressed above and in replies to ref #2.

  5. eLife

    eLife assessment

    This study addresses the role of FMRP in the migration of newborn neuroblasts in the postnatal brain. Through extensive and convincing analysis of living imaging videos, the authors showed that neurons with FMRP deletion migrate aberrantly and exhibit defects in nucleokinesis and centrokinesis. The study presents a valuable finding on the mechanism of neuroblast migration in the postnatal brain.

  6. eLife

    Reviewer #1 (Public Review):

    This study investigated Fragile X Messenger Ribonucleoprotein (FMRP) protein impact on neuroblast tangential migration in the postnatal rostral migratory stream (RMS). Authors conducted a series of live-imaging on organotypic brain slices from Fmr1-null mice. They continued their analysis silencing Fmr1 exclusively from migrating neuroblasts using electroporation-mediated RNA interference method (MiRFmr1 KD). These impressive approaches show that neuroblasts tangential migration is impaired in Fmr1-null mice RMS and these defects are mostly recapitulated in the MiRFmr1neuroblasts. This nicely supports the idea that FMRP have a cell autonomous function in tangentially migrating neuroblasts. Authors also confirm that FMRP mRNA target Microtubule Associated Protein 1B (MAP1B) is overexpressed in the Fmr1-null mice RMS. They successfully use electroporation-mediated RNA interference method to silence Map1b in the Fmr1-null mice neuroblasts. This discreet and elaborate experiment rescues most of the migratory defects observed both in Fmr1-null and MiRFmr1neuroblasts. Altogether, these results strongly suggest that FMRP-MAP1B axis has an important role in regulation of the neuroblasts tangential migration in the RMS. Neurons move forward in cyclic saltatory manner which includes repeated steps of leading process extension, migration of the cell organelles and nuclear translocation. Authors reveal by analyzing the live-imaging data that FMRP-MAP1B axis is affecting movement of centrosome and nucleus during saltatory migration. An important part of the centrosome and nucleus movement is forces mediated by microtubule dynamics. Authors propose that FMRP regulate tangential migration via microtubule dynamics regulator MAP1B. This work provides valuable new information on regulation of the neuroblasts tangential saltatory migration. These findings also increase and improve our understanding of the issues involved in Fragile X Syndrome (FXS) disorders. The conclusions of this work are supported by the presented data.

    The current version of the study has improved substantially. Authors have enhanced the material and methods section including a more detailed section on the neuronal migration analysis. This amendment is a very valuable addition and strengthens the interpretation of the results, analysis and conclusions. Authors also have strengthened and clarified their results providing a more profound analysis of the migration directionality between controls, Fmr1-null, MiRFmr1 KD and MiRMap1b KD neuroblasts. They have incorporated new results in the study which elaborate FMRP and MAP1B participation in microtubule organization during tangential migration. Authors show that FMRP-MAP1B axis act on microtubule cage surrounding the nucleus. Microtubule cage participate on proper nuclear movement during neuron migration. These results emphasize more the interplay between FMRP, MAP1B, and the microtubule cytoskeleton. The authors have successfully expanded both the introduction and discussion sections of the manuscript.

  7. eLife

    Reviewer #3 (Public Review):

    Neuronal migration is one of the key processes for appropriate neuronal development. Defects in neuronal migration are associated with different brain disorders often accompanied by intellectual disabilities. Therefore, the study of the mechanisms involved in neuronal migration helps to understand the pathogenesis of some brain malformations and psychiatric disorders.

    FMRP is an RNA-binding protein implicated in RNA metabolism regulation and mRNA local translation. FMRP loss of function causes fragile X syndrome (FXS), the most common form of inherited intellectual disability. Previous studies have shown the role of FMRP in the multipolar to bipolar transition during the radial migration in the cortex and its possible relation with periventricular heterotopia and altered synaptic communication in humans with FXS. However, the role of FMRP in neuronal tangential migration is largely unknown. In this manuscript, the authors aim to decipher the role of FMRP in the tangential migration of neuroblasts along the rostral migratory stream (RMS) in the postnatal brain. By extensive live-imaging analysis of migrating neuroblasts along the RMS, they demonstrate the requirement of FMRP for neuroblast migration and centrosomal movement. These migratory defects are cell-autonomous and mediated by the microtubule-associated protein Map1b.

    Overall, the manuscript highlights the importance of FMRP in neuronal tangential migration. They performed an analysis of different aspects of migration such as nucleokinesis and cytokinesis in migrating neuroblasts from live-imaging videos. The authors have reinforced the results that associate defects in microtubule organization in Fmrp1 KO neurons and this rescue with the microtubule-associated protein Map1b. Overall, results concerning the role of Fmr1 in the tangential migration of neuroblasts are solid and convincing.

    However, the work is still quite incomplete. My main concern is still what are the functional consequences of delay in neuroblast migration in the integration and function of OB interneurons and this relation with FXS pathophysiology. An anatomical examination of the RMS in the Fmr1KO mice is still missing.

  8. Version published to 10.7554/elife.88782.1 on eLife
  9. eLife

    Author Response:

    We are grateful to the three referees for their overall positive evaluation of our work and valuable constructive suggestions. We will address their public reviews with utmost care, as well as their private recommendations.

    To Reviewer #1: thanks for the positive comments and for the appreciation of our « impressive approaches »

    • We will add a more comprehensive section of neuronal migration analysis in the Material and Methods section. Sorry for that regrettable lack of precision.

    • We will address the comments about the sinuosity index definition and interpretations.

    • We will enhance the clarity of our writing and delve deeper into the discussion. As mentioned to Reviewer #3, the brevity of the text was influenced by the Short report format.

    To Reviewer #2 : thanks for the overall positive appreciation.

    We will also consider the recommendations for authors with care.

    To Reviewer #3 : thanks a lot for the feedback.

    • We will further develop the introduction and discussion sections as suggested. Regrettably and as mentioned to Reviewer #1, we had to significantly condense them due to the space constraints imposed by the Short Report format.

    • We will attempt to overexpress Map1B in order to assess the potential phenotypic similarity to the Fmr1 null condition, as suggested. However, it is important to acknowledge that this experiment may not yield a definitive answer due to potential differences in the level of Map1B expression driven by a CMV promoter compared to its endogenous expression in Fmr1 null neurons, as well as variations in the subcellular distribution of the overexpressed Map1B.

    • Regarding the anatomical consequences of aberrant migration, we acknowledge that neither our present work nor our previous study by Scotto-Lomassesse et al. provide evidence in this regard, as pointed out by the reviewer. Indeed, the delayed neurons do reach the olfactory bulb based on our findings. However, other studies have demonstrated that a delay in migration can have important functional consequences (eg Bocchi et al, 2017 doi: 10.1038/s41467-017-01046-w). Accordingly, we will revise and moderate our conclusions on this specific point.

  10. eLife

    eLife assessment

    This study presents a valuable finding on the role of fragile X messenger ribonucleoprotein (FMRP) and its target the microtubule associated protein 18 (MAP1B) in postnatal tangential migration of neuroblasts. The study combined molecular genetics (FMRP knock-out mice) with acute inactivation of FRMP and MAP1B to conclusively support the notion that FMRP-dependent regulation of MAP1B is necessary for proper neuronal migration toward the olfactory bulb using the rostral migratory stream. The evidence supporting the claims of the authors is solid, although inclusion of additional controls for experiments and/or more rigorous description of the finding and conclusions would have strengthened the study. The work improves our knowledge of the molecular mechanisms that control how neurons migrate in the brain to reach their final destinations and confirms that cytoskeleton regulators are key players in this process. will be of interest to developmental neurobiologists.

  11. eLife

    Reviewer #1 (Public Review):

    This work investigated Fragile X Messenger Ribonucleoprotein (FMRP) protein impact on neuroblast tangential migration in the postnatal rostral migratory stream (RMS). Authors conducted series of live-imaging on organotypic brain slices from Fmr1-null mice. They continued their analysis silencing Fmr1 exclusively from migrating neuroblasts using electroporation-mediated RNA interference method (MiRFmr1 KD). These impressive approaches show that neuroblasts tangential migration is impaired in Fmr1-null mice RMS and these defects are mostly recapitulated in the MiRFmr1neuroblasts.This nicely supports the idea that FMRP have a cell autonomous function in tangentially migrating neuroblasts. It is an important part of this work as migrating neuroblasts are in contact with each other and surrounding glial cells while migrating towards the olfactory bulb. The authors also confirm that FMRP mRNA target Microtubule Associated Protein 1B (MAP1B) is overexpressed in the Fmr1-null mice RMS. They successfully use electroporation-mediated RNA interference method to silence Map1b in the Fmr1-null mice neuroblasts. This discreet and elaborate experiment rescues most of the migratory defects observed both in Fmr1-null and MiRFmr1neuroblasts. Altogether, these results strongly suggest that FMRP-MAP1B axis has an important role in regulation of the neuroblasts tangential migration in RMS. Neurons move forward in cyclic saltatory manner which includes repeated steps of leading process extension, migration of the cell organelles and nuclear translocation. Authors reveal by analyzing the live-imaging data that FMRP-MAP1B axis is affecting movement of centrosome and nucleus during saltatory migration. An important part of the centrosome and nucleus movement is forces mediated by microtubule dynamics. Authors propose that FMRP regulate tangential migration via microtubule dynamics regulator MAP1B. This work provides valuable new information on regulation of the neuroblasts tangential saltatory migration. These findings also increase and improve our understanding of the issues involved in Fragile X Syndrome (FXS) disorders. The conclusions of this work are mostly supported by the data. However, methods and data analysis would benefit from more careful and comprehensive scrutiny.

    1.) It would be beneficial for the detail-oriented readers to have a more comprehensive section of neuronal migration analysis. It would help to understand better the details of the results and analysis. For example, percentage of pausing time. Is neuroblast migration speed and pausing time (%) separated from each other? Does this mean that migration speed is measured from time of the nucleus movement, and it excludes pausing time? Sometimes migration speed refers to the total distance that cells have moved divided by the time between images (e.g., Nam et al. 2007, J Comp Neurol 505: 190-208). This is also important as neuroblasts migration speed fluctuate during their migration in RMS (e.g., Belvindrah et al. 2017, J Cell Biol 216: 2443-2461). It could be useful, for example, to show a plot of total migration distance distribution between controls, Fmr1-null, MiRFmr1 KD and MiRMap1b KD neuroblasts.

    2.) The author's claim that Fmr1 interfering RNA (MiFmr1 KD) model "recapitulates the entire migratory phenotype described in Fmr1-null mutants". This is evident from the data analysis for the migration speed, pausing time percentage and NK distance. Parallel, but slightly weaker effect is seen in, NK frequency, CK frequency and CK efficiency. However, interpretation of the directionality analysis causes some concerns.
    a) Sinuosity index
    Fmr1-null mice (ctr: 1.32{plus minus}0.04; Fmr1-null: 1.93{plus minus}0.16; Figure 2C) and MiFmr1 KD neurons (MiRNEG: 1.5{plus minus}0.12; MiRFmr1 KD 1.62 {plus minus}0.08; Figure S1C). The latter results are significant, but standard error of means (SEM) seems to overlap. In addition, there is only a minor difference between control and MiRFmr1 KD cells sinuosity index.
    b) Directionality radar
    Migration directionality radar seems to be considerably different between Fmr1-null (Figure 2D) and MiFmr1 KD results (Figure S1D).
    It would be beneficial for this article to fully disclose, how these analyses were performed. For example, how sinuosity index was calculated and what does it precisely measure. It would greatly help to understand better the directionality analysis. To make these results more solid authors could have used original migration trajectories in the rose and/or trajectory plots. These plots visualize better the migration directionality results and clarify the changes in the directionality during migration.

    3.) Authors claim that "Overall, our results demonstrate that MAP1B is the main FMRP mRNA target involved in the regulation of neuronal migration". Results and analysis show that migration speed, pausing time percentage, NK distance and NK frequency migratory defects are all rescued in Fmr1-null mice when MiRMap1b KD was introduced to the neuroblasts (Figure 4). These results are very interesting, linking FMRP-MAP1B axis to the microtubule dynamics.

    4.) Authors could refine in discussion what is known about FRMP in neuronal migration. For example, La Fata et al. 2014 found that N-cadherin protein levels were lower in Fmr1-null mice and reintroducing N-cadherin rescued embryonic radial migration defects. N-cadherin is also expressed in the RMS and its deficiency affects negatively to the neuroblast migration (e.g., Porlan et al. 2014, Nat Cell Biol (7):629-38). This relationship of FMRP and N-cadherin could be discussed and considered in the article more closely. Overall, the article will benefit from clearer writing and more comprehensive discussion.

  12. eLife

    Reviewer #2 (Public Review):

    In this manuscript, the authors conducted a straightforward molecular approach to link FMRP and MAP1B proteins functionally. Both proteins are connected since FMRP is a translational regulator of the MAP1B protein, a microtubule-stabilizing factor.

    The results combined molecular genetics (FMRP knock-out mice) with acute inactivation of FRMP and MAP1B to conclusively support the notion that FMRP-dependent regulation of MAP1B is necessary for proper neuronal migration toward the olfactory bulb using the rostral migratory stream.

    Overall, these results increase our knowledge of the molecular mechanism that controls how neurons migrate in the brain to reach their final destinations and confirms that cytoskeleton regulators are key players in this process.

  13. eLife

    Reviewer #3 (Public Review):

    Neuronal migration is one of the key processes for appropriate neuronal development. Defects in neuronal migration are associated with different brain disorders often accompanied by intellectual disabilities. Therefore, the study of the mechanisms involved in neuronal migration helps to understand the pathogenesis of some brain malformations and psychiatric disorders.

    FMRP is an RNA-binding protein implicated in RNA metabolism regulation and mRNA local translation. FMRP loss of function causes fragile X syndrome (FXS), the most common form of inherited intellectual disability. Previous studies have shown the role of FMRP in the multipolar to bipolar transition during the radial migration in the cortex and its possible relation with periventricular heterotopia and altered synaptic communication in humans with FXS. However, the role of FMRP in neuronal tangential migration is largely unknown. In this manuscript, the authors aim to decipher the role of FMRP in the tangential migration of neuroblasts along the rostral migratory stream (RMS) in the postnatal brain. By extensive live-imaging analysis of migrating neuroblasts along the RMS, they demonstrate the requirement of FMRP for neuroblast migration and centrosomal movement. These migratory defects are cell-autonomous and mediated by the microtubule-associated protein Map1b.

    Overall, the manuscript highlights the importance of FMRP in neuronal tangential migration. They performed an analysis of different aspects of migration such as nucleokinesis and cytokinesis in migrating neuroblasts from live-imaging videos.
    However, the work is quite incomplete. The role of FMRP and Map1b in neuronal migration is not well introduced and discussed. In the cortex, FMRP is mainly implicated in the multipolar to bipolar transition of immature neurons, but not in the migration itself (la Fata et al., 2014). In fact, Fmr1 KO mice do not show impairment in cortical lamination. On the other hand, very less is mentioned about the role of Map1b in neuronal migration. It is not shown whether overexpression of Map1b alters neuroblast migration and recapitulates the Fmr1 KO phenotype.

    Moreover, it is unclear to me which are the anatomical consequences of aberrant migration of neuroblasts in the Fmr1 KO mice. Authors mention that neuroblasts properly arrive at the OB and they refer to a previous publication (Scotto-Lomassese et al., 2011). However, this study does not show the distribution of neuroblasts in the SVZ, along the RMS or in the olfactory bulb (OB) in mutant mice. On the contrary, they said that there is no delay in the migration or maturation of granular cells arriving at the OB (Scotto-Lomassese et al., 2011). In summary, the authors do not show the functional consequences of aberrant neuroblast migration in the Fmr1 KO mice, making weaker the assumption that the study is important for the understanding of FXS pathophysiology.

  14. Version published to 10.1101/2023.03.06.530447 on bioRxiv