Genes, Gender, Environment, and Novel Functions of Estrogen Receptor Beta in the Susceptibility to Neurodevelopmental Disorders

Round 1

Reviewer 1 Report

The review manuscript by Varshney and Nalvarte describe the biological basis of sex differences in neurological disorders, with a particular focus on dyslexia. This has potential to attract attention as there are few papers that describe neurobiological basis of dyslexia in great detail.  The authors discuss the contribution of sex-chromosomes and sex-hormone as the basis of sex differences in neurological disorders, but mainly focussing on the role of estrogen receptor beta signalling. Whilst the paper generally reads well, it can be improved by attention to the following points.

1)     Although the title specifically states that it is focusing on dyslexia, there are no sections in the MS that describes dyslexia in detail. A specific section on dyslexia describing the prevalence, symptoms, neuroanatomy, neurochemistry, treatments and importantly, known sex differences in prevalence, progression, severity, etc, would help to guide the reader for the later sections.

2) The authors often use other neurodevelopment disorders (ADHD/ASD) to extrapolate their arguments for dyslexia / intellectual disability throughout the MS. Although ADHD/ASD has similar features to dyslexia (e.g. cognitive impairment), it is clearly a different neurodevelopment disorder. As mentioned in the previous point, the authors should focus on biological basis of dyslexia (as stated in the title) or change the focus of the MS to sex differences in neurodevelopmental disorders (which will also require a title change)

3) The section on Chromosomal: SRY is interesting but misses recent references that describes the regulation and function of SRY in male dopamine neurons (ie. Czech et al., 2012, J. Neurochem., Czech et al., 2012, Endocrinol; Lee ad Harley, 2012, Bioessays).

Author Response

We would like to thank the editors and the reviewers for taking interest and their time in reviewing this review article. The comments provided by the reviewers are well justified and we have addressed the raised issues. Our changes to the manuscript are highlighted in yellow. We believe that the manuscript has been strengthened and hope that it is now suitable for publication in Brain Sciences.

For the reviewers’ comments we have provided answers. Our answers are directly below the comments.

Reviewer 1

1)    Although the title specifically states that it is focusing on dyslexia, there are no sections in the MS that describes dyslexia in detail. A specific section on dyslexia describing the prevalence, symptoms, neuroanatomy, neurochemistry, treatments and importantly, known sex differences in prevalence, progression, severity, etc, would help to guide the reader for the later sections.

Reply: We agree. We have extended the section on dyslexia to include these descriptions (rows 210 – 220, 238 – 242), and included here that these data vary from different studies, warranting more studies with sex-stratified patient groups. We have also replaced “dyslexia” in the title to “neurodevelopmental disorders” (row 4) since the overall focus is not only on dyslexia, but also on other neurodevelopmental disorders.

2)    The authors often use other neurodevelopment disorders (ADHD/ASD) to extrapolate their arguments for dyslexia / intellectual disability throughout the MS. Although ADHD/ASD has similar features to dyslexia (e.g. cognitive impairment), it is clearly a different neurodevelopment disorder. As mentioned in the previous point, the authors should focus on biological basis of dyslexia (as stated in the title) or change the focus of the MS to sex differences in neurodevelopmental disorders (which will also require a title change)

Reply: The reviewer brings up a very important point. We agree. Although these cognitive impairment disorders have some symptoms in common, ADHD/ASD differ from dyslexia (now more clearly stated in rows 231 – 233). Nevertheless, the data (new and established) on ERbeta function summarized in the manuscript bring new knowledge to sex-specific differences in susceptibility to these neurodevelopmental disorders. Thus, the manuscript proposes that more studies are needed to describe the role of ERbeta in, not only dyslexia, but also in other neurodevelopmental disorders such as ADHD/ASD. Therefore, we have chosen to replace “dyslexia” in the title to “neurodevelopmental disorders” (row 4).

3)    The section on Chromosomal: SRY is interesting but misses recent references that describes the regulation and function of SRY in male dopamine neurons (ie. Czech et al., 2012, J. Neurochem., Czech et al., 2012, Endocrinol; Lee ad Harley, 2012, Bioessays).

Reply: We have added these references and also expanded this section to not only the SRY gene (rows 59 – 63 and 69 – 76).

Reviewer 2 Report

This is a review manuscript that describes the biological basis underlying sex differences in neurological disorders with a focus on estrogen receptor beta signaling and how it might underlie sex differences in dyslexia. The authors described the role of ERb in epigenetic remodeling and how endocrine disruptions can affect its signaling. Overall, the manuscript reads well but can be improved with the following points:

1.      The authors comprehensively discuss the link between ERb and how it could be linked to susceptibility to neurodevelopmental disorders focusing on DNA methylation and how endocrine disruptive chemicals can modulate its function. However, the authors have not described dyslexia and how the disorder is sexually dimorphic (ie prevalence, symptoms, progression, effectiveness of treatments) even though it is specifically stated in the title that the manuscript is focused on the disorder.

2.      The section entitled “Chromosomal effects: SRY” is rather one sided as it is focused solely on the SRY gene.  There have been studies showing other Y-chromosome genes and X-linked genes contributing to these sexual dimorphisms.

3.      Some of the points made in the manuscript were somewhat speculative as they were derived from evidence made in regards to ADHD or ASD instead of dyslexia, which although have some similar symptoms, they are different neurological disorders.

4.      There are a couple of spelling errors within the manuscript and the word “deregulation” should be replaced with “dysregulation,” which is probably more appropriate. 

Author Response

We would like to thank the editors and the reviewers for taking interest and their time in reviewing this review article. The comments provided by the reviewers are well justified and we have addressed the raised issues. Our changes to the manuscript are highlighted in yellow. We believe that the manuscript has been strengthened and hope that it is now suitable for publication in Brain Sciences.

For the reviewers’ comments we have provided answers. Our answers are directly below the comments.

Reviewer 2

1)    The authors comprehensively discuss the link between ERb and how it could be linked to susceptibility to neurodevelopmental disorders focusing on DNA methylation and how endocrine disruptive chemicals can modulate its function. However, the authors have not described dyslexia and how the disorder is sexually dimorphic (ie prevalence, symptoms, progression, effectiveness of treatments) even though it is specifically stated in the title that the manuscript is focused on the disorder.

Reply: This point was also raised by reviewer 1 and we have added this information (as far as known) to the dyslexia section (rows 210 – 220 and 238 – 242). We have also replaced “dyslexia” in the title to “neurodevelopmental disorders” (row 4) since the overall focus is not only on dyslexia, but also on other neurodevelopmental disorders.

2)    The section entitled “Chromosomal effects: SRY” is rather one sided as it is focused solely on the SRY gene.  There have been studies showing other Y-chromosome genes and X-linked genes contributing to these sexual dimorphisms.

Reply: We have expanded this section accordingly bringing up other chromosomal genes, the “chromosomal dosage” effects, and the function of SRY on regulating dopaminergic neurons (rows 59 – 63 and 69 – 76).

3)    Some of the points made in the manuscript were somewhat speculative as they were derived from evidence made in regards to ADHD or ASD instead of dyslexia, which although have some similar symptoms, they are different neurological disorders.

Reply: Yes, although these cognitive impairment disorders have some symptoms in common, ADHD/ASD differ from dyslexia (now added to rows 231 – 233). Nevertheless, the data on ERbeta function (new and established) summarized in the manuscript may bring new understanding to male and female susceptibility to these neurodevelopmental disorders (not only dyslexia). Thus, although speculative, the manuscript proposes that ERbeta may have a more central role in neurodevelopmental disorders than previously thought (e.g. be more protective in females, rows 233 – 237), and importantly, that more studies are therefore needed to describe the role of ERbeta in disorders such as dyslexia, ADHD, and ASD. Therefore, we have chosen to replace “dyslexia” in the title to “neurodevelopmental disorders” (row 4).

4)    There are a couple of spelling errors within the manuscript and the word “deregulation” should be replaced with “dysregulation,” which is probably more appropriate. 

Reply: We have gone through the manuscript and corrected this and other spelling errors.

We have also added acknowledgements, author contributions, and updated the reference list.

Round 2

Reviewer 1 Report

The authors have adequately addressed all the issues