Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis
Authors: Tania Attié-Bitach
Frédéric Laumonnier
Stanislas Lyonnet
Abdelhafid Natiq
Sylvain Briault
Abdelaziz Sefiani
Arnold Munnich
Aziza Sbiti
Capucine Picard
Abdellah Asermouh
Lekbir Baala
Heather C Etchevers
Nathalie Boddaert
Jeanne Amiel
Féréchté Encha-Razavi
Journal: Nature Genetics (2007)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Neural progenitor; proliferation; migration; brain size; neurogenesis
Affiliations: Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Maroc.

Abstract:  Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes. 

Retracted: No

PubPeer comments:
 I am surprised by the cases reported by Baala et al. ![file] I guess this is a sagittal section of the brain on T1-weighted sequence. The cerebellum does not seem to be hypoplastic (yellow arrow) whereas the spinal cord seems to be hypoplastic (red arrow). ![file] What is the sequence of this section? What is the plane of section? It is not very professional to publish without these informations. This sequence is not good enough to be certain that the lesion is indeed polymicrogyria. How the authors conclude this? ![file] I guess this is an axial section on T2-weighted sequence. The correct naming of the figure is  i instead of  g . The white arrow does not point to the anterior arm of internal capsule. Basal ganglia? Even in genetics journal, it is important to make correct description of the radiological data. , 
 Another surprise #1 ![file] Looking the pedigree is highly suggestive for an autosomal recessive disease. ![file] Why such a conclusion? , 
 The expression pattern proposed by the authors is a matter of concern. ![file] The legend is wrong: c-e are parasagittal sections (Carnegie stage 19) whereas f-i are sections of a brain from a fetus (12.5 weeks of development). ![file] Sagittal sections of a Carnegie stage 17 are presented here. The sections presented by the authors are parasagittal sections. The floor plate cannot be evidenced by this type of sections as evidenced here: ![file] Thus, expression pattern of this gene does not correspond to forebrain basal floor plate. This should be corrected. ![file] It is impossible to recognize the structures presented in these sections. The cortex seems to be very infolded by the technics. The structure highlighted in i is difficult to recognize. How can the authors be sure that these structures are the ganglionic eminence? , 
 I thank the post-publication reviewers for the time they have taken to critically examine this article on which I was a co-author, where my personal contribution fourteen years ago was relative to the expression domain of *EOMES* during human embryonic early fetal development. I canu2019t answer the first remark about the MRI but will bring it to the attention of the neuroradiologist at the time. For the second comment about the wording of the inheritance hypothesis, our work seems to have concluded that there is indeed autosomal recessive disease due to the translocation described, which leads to no transcription of *EOMES*. In a heterozygous relative, there was transcription only from the unrearranged allele. I agree that the use of the word u201cDespiteu201d is confusing here, though. The third commentary about the *in situ* hybridization pattern is one I am best qualified to answer. I agree with the reviewer that u201cThe sections presented by the authors are parasagittal sections. The floor plate cannot be evidenced by this type of sections as evidenced hereu201d u2013 particularly as I went looking for the original images (and did not find them u2013 they are perhaps on CDs) but I did find a working document from the first author in which these same images were indeed presented as u201cparasagittalu201d. The restricted signal represented may be real or may be an artifact, and the region to which it corresponds in the ventricular zone is not clear. As the reviewer also points out, itu2019s not simple to identify structures in the early fetal brain tissue that had been hybridized here. The signal itself appears convincingly positive. In the working document to which Iu2019d referred before, there was also a hematoxylin-eosin stain and a slightly wider view than what had finished in this article. I attach the image. It is my opinion that it remains likely that this was indeed a ganglionic eminence as it does not appear laminar, but thicker and more ventral than the cortical areas. ![file] Finally, I would like to state that although the Necker Embryology resource is no longer operational for lack of funding, the Human Developmental Biology Resource (HDBR) has been strongly supported over the years and continues to make samples available to researchers for further study and independent confirmation of data pertaining to human development (http: www.hdbr.org registration-forms). Thank you to the reviewers for the discussion and opportunity to make these clarifications. ,