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(A–D) Examples of brain cryosection pictures used for the 3D reconstruction. (E–H) 3D reconstruction models of 17 (E, F) and 19 (G, H) GW, with and without highlighted dissected regions PFO (red) and PT (green). (I–L) Microdissected regions of PFO (I, K) and PT (J, L) areas at 17 (I, J) and 19 (K, L) GW, highlighted on top of cresyl violet-stained sections. Scale bar: 1 cm.
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The developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel a...
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... Embryonic/fetal thyroid were collected from human embryos after elective termination of pregnancy at 9-13 weeks post amenorrhea (corresponding to 7-11 weeks of gestation) according to a protocol approved by the three relevant Ethics Committees (Erasme Hospital, Université Libre de Bruxelles, and Belgian National Fund for Scientific Research FRS/FNRS) on research involving human subjects. Written informed consent was given by the woman in each case; fetal thyroid material was collected from fetuses used in another study concerning brain development (Lambert et al., 2011). Donors did not have any known thyroid pathology nor other known health anomaly. ...
... eu/ servi ce/ jugex/). Since previous research claimed the involvement of the AG in language processing, we focused on genetic expression of languagerelated genes, i.e., FOXP2 and ATP2C2 (Lai et al. 2003;Newbury and Monaco 2010;Lambert et al. 2011;Unger et al. 2021a, b). While FOXP2 is supposed to be involved in the development of speech and language, ATP2C2 has been associated with dyslexia and other communication disorders (Lai et al. 2003;Newbury and Monaco 2010;Lambert et al. 2011;Unger et al. 2021a, b). ...
... Since previous research claimed the involvement of the AG in language processing, we focused on genetic expression of languagerelated genes, i.e., FOXP2 and ATP2C2 (Lai et al. 2003;Newbury and Monaco 2010;Lambert et al. 2011;Unger et al. 2021a, b). While FOXP2 is supposed to be involved in the development of speech and language, ATP2C2 has been associated with dyslexia and other communication disorders (Lai et al. 2003;Newbury and Monaco 2010;Lambert et al. 2011;Unger et al. 2021a, b). ...
... Generally, area PGa shows a higher expression of ATP2C2 (with higher right as compared to left hemispheric expression) and a lower expression of FOXP2 as compared to area PGp. Since both genes are supposed to support successful language processing during the lifespan [i.e., FOXP2 is supposed to be involved in the development of speech and language, ATP2C2 has been associated with dyslexia and other communication disorders (Lai et al. 2003;Newbury and Monaco 2010;Lambert et al. 2011;Unger et al. 2021a, b)], the difference in gene expression may suggest a functional diversity to exist between areas PGa and PGp. These results, indeed, align with the functional diversity found between these areas, especially in the right hemispheric AG, i.e., area PGa is related to semantic fluency, whereas area PGp shows no correlation with semantic fluency. ...
The angular gyrus (AG) has been associated with multiple cognitive functions, such as language, spatial and memory functions. Since the AG is thought to be a cross-modal hub region suffering from significant age-related structural atrophy, it may also play a key role in age-related cognitive decline. However, the exact relation between structural atrophy of the AG and cognitive decline in older adults is not fully understood, which may be related to two aspects: First, the AG is cytoarchitectonically divided into two areas, PGa and PGp, potentially sub-serving different cognitive functions. Second, the older adult population is characterized by high between-subjects variability which requires targeting individual phenomena during the aging process. We therefore performed a multimodal (gray matter volume [GMV], resting-state functional connectivity [RSFC] and structural connectivity [SC]) characterization of AG subdivisions PGa and PGp in a large older adult population, together with relations to age, cognition and lifestyle on the group level. Afterwards, we switched the perspective to the individual, which is especially important when it comes to the assessment of individual patients. The AG can be considered a heterogeneous structure in of the older brain: we found the different AG parts to be associated with different patterns of whole-brain GMV associations as well as their associations with RSFC, and SC patterns. Similarly, differential effects of age, cognition and lifestyle on the GMV of AG subdivisions were observed. This suggests each region to be structurally and functionally differentially involved in the older adult’s brain network architecture, which was supported by differential molecular and genetic patterns, derived from the EBRAINS multilevel atlas framework. Importantly, individual profiles deviated considerably from the global conclusion drawn from the group study. Hence, general observations within the older adult population need to be carefully considered, when addressing individual conditions in clinical practice.
... 80,96,97 In contrast, other studies have found global symmetry in gene expression during development, but these were conducted in small sample sizes. 98,99 This adds further support to an epigenetic origin of lateralization early in development, though more research is needed. ...
The lateralization of the human brain may provide clues into the pathogenesis and progression of neurodegenerative diseases. Though differing in their presentation and underlying pathologies, neurodegenerative diseases are all devastating and share an intriguing theme of asymmetrical pathology and clinical symptoms. Parkinson’s disease, with its distinctive onset of motor symptoms on one side of the body, stands out in this regard, but a review of the literature reveals asymmetries in several other neurodegenerative diseases. Here we review the lateralization of the structure and function of the healthy human brain and the common genetic and epigenetic patterns contributing to the development of asymmetry in health and disease. We specifically examine the role of asymmetry in Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, and interrogate whether these imbalances may reveal meaningful clues about the origins of these diseases. We also propose several hypotheses for how lateralization may contribute to the distinctive and enigmatic features of asymmetry in neurodegenerative diseases, suggesting a role for asymmetry in the choroid plexus, neurochemistry, protein distribution, brain connectivity, and the vagus nerve. Finally, we suggest how future studies may reveal novel insights into these diseases through the lens of asymmetry.
... Johnson et al. (2009) screened different brain regions in human fetuses including the perisylvian cortex (ventrolateral prefrontal, motor-somatosensory, parietal association, temporal auditory), where FOXP2 showed a modest upregulation. Lambert et al. (2011) directly screened precursor structures of Broca's and Wernicke's regions in the fetal brain and found several FOXP2 regulated genes among the differentially expressed genes. An overview of the other recent studies on Broca's and Wernicke's regions in humans and model organisms is provided by Supplementary Table 2. ...
Impaired phonological processing is a leading symptom of multifactorial language and learning disorders suggesting a common biological basis. Here we evaluated studies of dyslexia, dyscalculia, specific language impairment (SLI), and the logopenic variant of primary progressive aphasia (lvPPA) seeking for shared risk genes in Broca’s and Wernicke’s regions, being key for phonological processing within the complex language network. The identified “phonology-related genes” from literature were functionally characterized using Atlas-based expression mapping (JuGEx) and gene set enrichment. Out of 643 publications from the last decade until now, we extracted 21 candidate genes of which 13 overlapped with dyslexia and SLI, six with dyslexia and dyscalculia, and two with dyslexia, dyscalculia, and SLI. No overlap was observed between the childhood disorders and the late-onset lvPPA often showing symptoms of learning disorders earlier in life. Multiple genes were enriched in Gene Ontology terms of the topics learning (CNTNAP2, CYFIP1, DCDC2, DNAAF4, FOXP2) and neuronal development (CCDC136, CNTNAP2, CYFIP1, DCDC2, KIAA0319, RBFOX2, ROBO1). Twelve genes showed above-average expression across both regions indicating moderate-to-high gene activity in the investigated cortical part of the language network. Of these, three genes were differentially expressed suggesting potential regional specializations: ATP2C2 was upregulated in Broca’s region, while DNAAF4 and FOXP2 were upregulated in Wernicke’s region. ATP2C2 encodes a magnesium-dependent calcium transporter which fits with reports about disturbed calcium and magnesium levels for dyslexia and other communication disorders. DNAAF4 (formerly known as DYX1C1) is involved in neuronal migration supporting the hypothesis of disturbed migration in dyslexia. FOXP2 is a transcription factor that regulates a number of genes involved in development of speech and language. Overall, our interdisciplinary and multi-tiered approach provided evidence that genetic and transcriptional variation of ATP2C2, DNAAF4, and FOXP2 may play a role in physiological and pathological aspects of phonological processing.
... Embryonic/fetal thyroid were collected from human embryos after elective termination of pregnancy at 9-13 weeks post amenorrhea (corresponding to 7-11 weeks of gestation) according to a protocol approved by the three relevant Ethics Committees (Erasme Hospital, Université Libre de Bruxelles, and Belgian National Fund for Scientific Research FRS/FNRS) on research involving human subjects. Written informed consent was given by the woman in each case; fetal thyroid material was collected from fetuses used in another study concerning brain development (Lambert et al., 2011). Donors did not have any known thyroid pathology nor other known health anomaly. ...
The human thyroid gland acquires a differentiation program as early as weeks 3–4 of embryonic development. The onset of functional differentiation, which manifests by the appearance of colloid in thyroid follicles, takes place during gestation weeks 10–11. By 12–13 weeks functional differentiation is accomplished and the thyroid is capable of producing thyroid hormones although at a low level. During maturation, thyroid hormones yield increases and physiological mechanisms of thyroid hormone synthesis regulation are established. In the present work we traced the process of thyroid functional differentiation and maturation in the course of human development by performing transcriptomic analysis of human thyroids covering the period of gestation weeks 7–11 and comparing it to adult human thyroid. We obtained specific transcriptomic signatures of embryonic and adult human thyroids by comparing them to non-thyroid tissues from human embryos and adults. We defined a non-TSH (thyroid stimulating hormone) dependent transition from differentiation to maturation of thyroid. The study also sought to shed light on possible factors that could replace TSH, which is absent in this window of gestational age, to trigger transition to the emergence of thyroid function. We propose a list of possible genes that may also be involved in abnormalities in thyroid differentiation and/or maturation, hence leading to congenital hypothyroidism. To our knowledge, this study represent the first transcriptomic analysis of human embryonic thyroid and its comparison to adult thyroid.
... Although the exact nature of this association cannot be further clarified in the scope of this study, this observation is another strong indicator of the large-scale neurodevelopmental impact of callosal connectivity on the establishment of human brain asymmetry (Hinkley et al. 2012). Global cortical gene expression profiles seem to be generally symmetrical at fetal and adult stages (Johnson et al. 2009;Kang et al. 2011;Lambert et al. 2011;Hawrylycz et al. 2012;Pletikos et al. 2014). After restricting the analysis to structurally strongly asymmetric brain regions (Sun et al. 2005;Karlebach and Francks 2015), strongly lateralized genes could be Overall discriminability is similar between all subsets of ACC (a). ...
Genetic, molecular, and physical forces together impact brain morphogenesis. The early impact of deficient midline crossing in agenesis of the Corpus Callosum (ACC) on prenatal human brain development and architecture is widely unknown. Here we analyze the changes of brain structure in 46 fetuses with ACC in vivo to identify their deviations from normal development. Cases of complete ACC show an increase in the thickness of the cerebral wall in the frontomedial regions and a reduction in the temporal, insular, medial occipital and lateral parietal regions, already present at midgestation. ACC is associated with a more symmetric configuration of the temporal lobes and increased frequency of atypical asymmetry patterns, indicating an early morphomechanic effect of callosal growth on human brain development affecting the thickness of the pallium along a ventro-dorsal gradient. Altered prenatal brain architecture in ACC emphasizes the importance of conformational forces introduced by emerging interhemispheric connectivity on the establishment of polygenically determined brain asymmetries.
... Most explanatory models are based on research in only distantly related animal models, such as the zebrafish, in which side-differentiated nodal (a TGFβ signaling molecule) activity has been observed during the development of asymmetry (Duboc et al. 2015;Grimes and Burdine 2017;Güntürkün and Ocklenburg 2017). Despite hemispheric differences in the transcription of specific genes, accentuated in the auditory and the superior temporal cortices of adults and fetuses (Karlebach and Francks 2015), the majority of studies were unable to find hemispheric differences either on the level of individual gene expression, or in the context of the temporal trajectories of global gene expression patterns (Lambert et al. 2011;Pletikos et al. 2014), or mRNA expression profiles (Johnson et al. 2009). ...
Knowledge about structural brain asymmetries of human fetuses with body lateralization defects—congenital diseases in which visceral organs are partially or completely incorrectly positioned—can improve our understanding of the developmental origins of hemispheric brain asymmetry. This study investigated structural brain asymmetry in 21 fetuses, which were diagnosed with different types of lateralization defects; 5 fetuses with ciliopathies and 26 age-matched healthy control cases, between 22 and 34 gestational weeks of age. For this purpose, a database of 4007 fetal magnetic resonance imagings (MRIs) was accessed and searched for the corresponding diagnoses. Specific temporal lobe brain asymmetry indices were quantified using in vivo, super-resolution-processed MR brain imaging data. Results revealed that the perisylvian fetal structural brain lateralization patterns and asymmetry indices did not differ between cases with lateralization defects, ciliopathies, and normal controls. Molecular mechanisms involved in the definition of the right/left body axis—including cilium-dependent lateralization processes—appear to occur independently from those involved in the early establishment of structural human brain asymmetries. Atypically inverted early structural brain asymmetries are similarly rare in individuals with lateralization defects and may have a complex, multifactorial, and neurodevelopmental background with currently unknown postnatal functional consequences.
... While little is known about the precise genetic mechanisms behind the expansion of functional cortical regions in humans, gene expression studies have revealed patterns of gene products that are enriched in certain portions of the brain relative to others. We know, for instance, that the genes including NR4A2 and CNTN4 are both expressed in the superficial portion of the cortical plate during development and that NR4A2 has higher expression levels in the parieto-occipito-temporal region of cortex, while CNTN4 has higher expression in the prefrontal/frontal/orbito-frontal region of cortex (Lambert et al. 2011). Such studies provide candidate genes for the evolutionary expansion in association regions of the human cortex, though evidence for genetic sequence changes between humans and chimpanzees among these candidate genes is limited. ...
... They can overlap with the abovementioned HARs [50]. HACNs are enriched near genes related to neuronal functioning, such as neuronal cell adhesion [49] and brain development [100]. Based on structural analyses of HACNs, HARs and their genomic contexts, around one third of them was predicted to be developmental enhancers [50]. ...
... On the other hand, changes in gene regulation could be limited to a certain tissue or time frame that can enable fine tuning of a gene activity [105]. Indeed, the fast-evolving sequences (HARs or HACNs) are often found close to the genes active during embryo-and neurogenesis [48][49][50]100]. For example, HACNS1 (HAR2) demonstrates greater enhancer activity in limb buds of transgenic mice compared to orthologous sequences from chimpanzee or rhesus macaque [106]. ...
Chimpanzees are the closest living relatives of humans. The divergence between human and chimpanzee ancestors dates to approximately 6,5-7,5 million years ago. Genetic features distinguishing us from chimpanzees and making us humans are still of a great interest. After divergence of their ancestor lineages, human and chimpanzee genomes underwent multiple changes including single nucleotide substitutions, deletions and duplications of DNA fragments of different size, insertion of transposable elements and chromosomal rearrangements. Human-specific single nucleotide alterations constituted 1.23% of human DNA, whereas more extended deletions and insertions cover ~ 3% of our genome. Moreover, much higher proportion is made by differential chromosomal inversions and translocations comprising several megabase-long regions or even whole chromosomes. However, despite of extensive knowledge of structural genomic changes accompanying human evolution we still cannot identify with certainty the causative genes of human identity. Most structural gene-influential changes happened at the level of expression regulation, which in turn provoked larger alterations of interactome gene regulation networks. In this review, we summarized the available information about genetic differences between humans and chimpanzees and their potential functional impacts on differential molecular, anatomical, physiological and cognitive peculiarities of these species.
... The most rapid production of myelin occurs during prenatal and early infant development (Lenroot and Giedd, 2006), in conjunction with dynamic changes in gene expression in brain tissue (Naumova et al., 2013). Studies of whole-genome expression in the developing brain reveal that the temporal dynamics of the transcriptome are more robust during prenatal development than at any postnatal stage (Colantuoni et al., 2011;Johnson et al., 2009;Kang et al., 2011;Lambert et al., 2011;Somel et al., 2010). Moreover, candidate susceptibility genes for speech and language disorders show an especially prominent window of expression during prenatal development in the perisylvian cortex, the part of the brain that encompasses the neural basis of language (Abrahams et al., 2007;Johnson et al., 2009). ...
... The present findings carry implications for language development as a process of refinement that builds upon a pre-existing structural scaffold in infancy, but also point towards a multitude of future questions. Our data support notions of the early impact of genetic susceptibility, as temporal dynamics of the transcriptome are known to be most robust during prenatal development relative to postnatal stages (Colantuoni et al., 2011;Johnson et al., 2009;Kang et al., 2011;Lambert et al., 2011;Somel et al., 2010). This is also reflected in the trajectory of white matter development, as the first two years of life signify the most rapid developmental period (Gilmore et al., 2018). ...
... Diffusion-weighted images were processed with the approach taken in a previous study from our lab with infants from this cohort (Langer et al., 2015). A brain mask was generated from the structural T1-weighted image utilizing the Brain Extraction Tool (BET, Smith, 2002) to separate brain tissue from nonbrain tissue. ...
Language acquisition is of central importance to a child's development. Although the trajectory of acquisition is shaped by input and experience postnatally, the neural basis for language emerges prenatally. Thus a fundamental question remains unexamined: to what extent may the structural foundations for language established in infancy predict long-term language abilities? In this longitudinal neuroimaging investigation of children from infancy to kindergarten, we find that white matter organization in infancy is prospectively associated with subsequent language abilities, specifically between: (i) the left arcuate fasciculus in infancy and subsequent phonological awareness and vocabulary knowledge, and (ii) the left corticospinal tract in infancy and phonological awareness and phonological memory in kindergarten. Results are independent of age and home literacy environment. These findings directly link white matter organization in infancy with language abilities after school entry, and suggest that structural organization in infancy sets an important foundation for subsequent language development.
