Defective Neural Stem and Progenitor Cell Proliferation in Neurodevelopmental Disorders
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn this article, the authors relate genetic and environmental factors on cell cycle progression to neurodevelopmental disorders through the biology of NSPC.
Broadly, this article is useful synthesis of the existing literature on varied signaling pathways, including delta/notch, Wnt, growth factors, transcription factors, and chromatin, as they relate to NSPC cell cycle progress and emergent microcephaly/macrocephaly.
The article would benefit from minor revision prior to publication.
Overall, it would be worth discussing more clearly, given the heavy focus on macro or microcepahly, to whether NDDs such ASD are specifically overenriched in micro and or macrocephalic conditions per se. That is what is the extent to which NDDs and microcephaly are co-morbid with each other?
To what extent are the NDD affiliated genes that impact NSPC biology, specifically associcated with NSPC phenotypes and not , more broadly, other types of stem/progenitor cells?
Minor comments include:
Although a laudable goal, it is difficult to imagine how drugs that may manipulate cell cycle progress could be repurposed to treat NDDs by altering NSPCs, when the NSPC biology is essentially complete by birth, and NDD diagnoses would be postnatal.
Line 298 please spell out on first use KBF re phenotypes
Further subheadings or other textual organizers in section 4.1 are recommended so that it reads less like a list.
Author Response
We sincerely appreciate your thorough review of our manuscript. Your insightful comments have been invaluable in enhancing the quality and clarity of our work. Below, we provide detailed responses and indicate the corresponding revisions, which are highlighted in the revised manuscript.
Comment: “In this article, the authors relate genetic and environmental factors on cell cycle progression to neurodevelopmental disorders through the biology of NSPC. Broadly, this article is useful synthesis of the existing literature on varied signaling pathways, including delta/notch, Wnt, growth factors, transcription factors, and chromatin, as they relate to NSPC cell cycle progress and emergent microcephaly/macrocephaly. The article would benefit from minor revision prior to publication.”
Response: Thank you very much for your positive and encouraging evaluation.
Comment: “Overall, it would be worth discussing more clearly, given the heavy focus on macro or microcepahly, to whether NDDs such ASD are specifically overenriched in micro and or macrocephalic conditions per se. That is what is the extent to which NDDs and microcephaly are co-morbid with each other?”
Response: Thank you for this excellent suggestion. It is estimated that 15–79% of individuals with NDDs exhibit comorbid microcephaly, while 54–67% of patients with microcephaly present with NDDs, indicating that microcephaly constitutes a frequent and clinically significant comorbidity of NDDs. Furthermore, approximately 16–22% of individuals with NDDs display comorbid macrocephaly, and 17% of patients with macrocephaly are diagnosed with NDDs, suggesting that macrocephaly also represents a relatively common and noteworthy comorbid condition, albeit with a weaker correlation compared to microcephaly. We have incorporated this discussion into the revised manuscript (page 3, lines 74–81).
Added sentences (page 3, lines 74–81):
“It is estimated that 15–79% of individuals with neurodevelopmental disorders (NDDs) exhibit comorbid microcephaly [27, 28], while 54–67% of patients with microcephaly present with NDDs [27, 29], indicating that microcephaly constitutes a frequent and clinically significant comorbidity of NDDs. Furthermore, approximately 16–22% of individuals with NDDs display comorbid macrocephaly [30, 31], and 17% of patients with macrocephaly are diagnosed with NDDs [32], suggesting that macrocephaly also represents a relatively common and noteworthy comorbid condition, albeit with a weaker correlation compared to microcephaly.”
Comment: “To what extent are the NDD affiliated genes that impact NSPC biology, specifically associated with NSPC phenotypes and not, more broadly, other types of stem/progenitor cells?”
Response: We appreciate this insightful question. Quantitatively determining how many NDD-affiliated genes specifically affect NSPCs, as opposed to other stem cell populations, remains difficult, as many of these genes have not been systematically examined in other cellular contexts. Epidemiological studies indicate that individuals with NDDs exhibit an elevated susceptibility to various forms of cancer, and approximately one-third of NDD risk genes overlap with cancer driver genes, implying that NDD-associated genes can also influence other stem cell populations. We have added this discussion to the revised manuscript (page 12, lines 389–395).
Added sentences (page 12, lines 389–395):
“Cell cycle regulation is not unique to NSPCs. Notably, epidemiological studies indicate that individuals with NDDs exhibit an elevated susceptibility to various forms of cancer [156-159], and approximately one-third of NDD risk genes overlap with cancer driver genes [160]. These finding suggest that NDD-associated genes may influence not only neural but also other stem cell populations. Elucidating the roles of NDD-affiliated genes in diverse stem cell types will provide deeper insight into both their shared and cell type–specific functions, as well as the selective vulnerability of distinct stem cell lineages.”
Comment: “Minor comments include: Although a laudable goal, it is difficult to imagine how drugs that may manipulate cell cycle progress could be repurposed to treat NDDs by altering NSPCs, when the NSPC biology is essentially complete by birth, and NDD diagnoses would be postnatal.”
Response: We fully agree that most NSPC biology is completed by birth, making direct postnatal pharmacological modulation of NSPC proliferation challenging. Therefore, we propose that prenatal genetic diagnosis of NDD-related mutations might be essential for the effective implementation of NSPC-targeted therapeutic strategies. Additionally, although not elaborated upon in this review to avoid digression, NSPCs are known to persist and remain functionally relevant in specific postnatal brain regions, including the subventricular zone and hippocampal dentate gyrus. These residual progenitor populations contribute to postnatal brain plasticity, which may influence the expression of NDD phenotypes. Consequently, targeting the cell cycle progression of these postnatal NSPCs could represent a potential strategy for ameliorating NDD phenotypes even after diagnosis. We have incorporated this discussion in the revised manuscript (page 12, lines 405–408).
Added sentences (page 12, lines 405–408):
“Nevertheless, because most NSPC proliferation is completed by birth, direct postnatal pharmacological intervention remains challenging. Therefore, prenatal genetic diagnosis of NDD-related mutations may be crucial for the effective application of NSPC-targeted therapeutic strategies.”
Comment: “Line 298 please spell out on first use KBF re phenotypes”
Response: The “KBG” designation originates from the initials of the surnames of the three families originally described with the condition. We have added this information in the revised manuscript (page 10, line 309–311).
Added sentences (page 10, lines 309–311):
“KBG designation originates from the initials of the surnames of the three families original-ly described with the condition.[127].”
Comment: “Further subheadings or other textual organizers in section 4.1 are recommended so that it reads less like a list.”
Response: We have added subheadings to section 4.1 to enhance readability and structure:
4.1.1 Signaling pathways (page 6, lines 176)
4.1.2 Transcription factors (page 8, lines 242)
4.1.3 Chromatin remodelers (page 9, lines 275)
4.1.4 Centrosomal and spindle proteins (page 10, lines 322)
Reviewer 2 Report
Comments and Suggestions for AuthorsThe review entitled “Defective Neural Stem and Progenitor Cell Proliferation in Neurodevelopmental Disorders” provides a comprehensive overview of the role of impaired proliferation of neural stem and progenitor cells (NSPCs) in the pathogenesis of neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder.
The review includes data from human brain organoid models, genetic studies, and animal research to deep into key signaling pathways involving Notch, Wnt, SHH, PI3K–mTOR; transcriptional regulators as PAX6, CHD8, SETD5, ANKRD11; and environmental teratogens (Zika virus, valproic acid, phenylketonuria).
The manuscript is well-structured and clearly articulated, with illustrative figures that effectively convey complex molecular mechanisms, thereby enhancing the readability and comprehension of the text.
However, several aspects warrant improvement:
- While the review thoroughly addresses NSPC proliferation, it provides limited discussion on other critical aspects of NSPC biology, such as migration, differentiation, and synaptogenesis. Authors should include some information on these other NSPC crutial aspects to offer a more wide view of NSPC dysfunction in NDDs.
- The manuscript contains a high density of abbreviations, many of which are not defined upon first use. To improve clarity, the authors should include a comprehensive list of abbreviations with their full definitions, for instance as an appendix.
Author Response
We sincerely thank you for your constructive comments, which have greatly contributed to refining our manuscript. Detailed responses to your suggestions are provided below, with corresponding revisions highlighted in the revised manuscript.
Comment: “The review entitled “Defective Neural Stem and Progenitor Cell Proliferation in Neurodevelopmental Disorders” provides a comprehensive overview of the role of impaired proliferation of neural stem and progenitor cells (NSPCs) in the pathogenesis of neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. The review includes data from human brain organoid models, genetic studies, and animal research to deep into key signaling pathways involving Notch, Wnt, SHH, PI3K–mTOR; transcriptional regulators as PAX6, CHD8, SETD5, ANKRD11; and environmental teratogens (Zika virus, valproic acid, phenylketonuria). The manuscript is well-structured and clearly articulated, with illustrative figures that effectively convey complex molecular mechanisms, thereby enhancing the readability and comprehension of the text. However, several aspects warrant improvement:”
Response: We are grateful for your positive and encouraging feedback.
Comment: “While the review thoroughly addresses NSPC proliferation, it provides limited discussion on other critical aspects of NSPC biology, such as migration, differentiation, and synaptogenesis. Authors should include some information on these other NSPC crutial aspects to offer a more wide view of NSPC dysfunction in NDDs.”
Response: We appreciate this valuable suggestion and have incorporated additional discussion on other aspects of NSPC biology beyond proliferation (page 12, lines 409–421).
Added sentences (page 12, lines 409–421):
“In addition to proliferation, other facets of NSPC biology are crucial for proper brain development, and their dysregulation has been implicated in NDDs. For instance, aberrant migration of NSPCs caused by mutations in more than 30 genes, including several tubulin and actin genes, leads to cortical malformations and mislamination, resulting in a smooth brain surface (lissencephaly) associated with NDDs [161]. Likewise, disrupted differentia-tion balance between neuronal and glial lineages contributes to abnormal synaptogenesis, cortical circuit assembly, and network connectivity [162, 163]. Collectively, these findings indicate that perturbations at every stage of NSPC biology—proliferation, differentiation, and migration—contribute to NDD pathogenesis. As discussed in this review, these pro-cesses are closely linked to cell cycle progression. Elucidating their molecular interconnec-tions is crucial for understanding the intricate mechanisms underlying NDD pathogenesis associated with NSPC dysfunction. We hope this review will inspire researchers in the field to address these critical knowledge gaps.”
Comment: “The manuscript contains a high density of abbreviations, many of which are not defined upon first use. To improve clarity, the authors should include a comprehensive list of abbreviations with their full definitions, for instance as an appendix.”
Response: We have added a comprehensive list of abbreviations as an appendix in the revised manuscript (pages 13–14).
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has been revised in accordance with the reviewer’s suggestions and, in its current form, it is suitable for publication.
