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Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice.

ABSTRACT: Proper formation of area identities of the cerebral cortex is crucial for cognitive functions and social behaviors of the brain. It remains largely unknown whether epigenetic mechanisms, including histone methylation, regulate cortical arealization. Here, we removed SETD2, the methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and showed that Setd2 is required for proper cortical arealization and the formation of cortico-thalamo-cortical circuits. Moreover, Setd2 conditional knockout mice exhibit defects in social interaction, motor learning, and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing SETD2 mutations. SETD2 maintains the expression of clustered protocadherin (cPcdh) genes in an H3K36me3 methyltransferase-dependent manner. Aberrant cortical arealization was recapitulated in cPcdh heterozygous mice. Together, our study emphasizes epigenetic mechanisms underlying cortical arealization and pathogenesis of the Sotos-like syndrome.

SUBMITTER: Xu L

PROVIDER: S-EPMC7775761 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sotos syndrome is an overgrowth condition characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and various degrees of learning difficulty, and associated with variable minor features. The exact prevalence remains unknown but hundreds of cases have been reported. The diagnosis is usually suspected after birth because of excessive height and occipitofrontal circumference (OFC), advanced bone age, neonatal complications including hypotonia and feeding difficulties, and facial gestalt. Other inconstant clinical abnormalities include scoliosis, cardiac and genitourinary anomalies, seizures and brisk deep tendon reflexes. Variable delays in cognitive and motor development are also observed. The syndrome may also be associated with an increased risk of tumors. Mutations and deletions of the NSD1 gene (located at chromosome 5q35 and coding for a histone methyltransferase implicated in transcriptional regulation) are responsible for more than 75% of cases. FISH analysis, MLPA or multiplex quantitative PCR allow the detection of total/partial NSD1 deletions, and direct sequencing allows detection of NSD1 mutations. The large majority of NSD1 abnormalities occur de novo and there are very few familial cases. Although most cases are sporadic, several reports of autosomal dominant inheritance have been described. Germline mosaicism has never been reported and the recurrence risk for normal parents is very low (<1%). The main differential diagnoses are Weaver syndrome, Beckwith-Wiedeman syndrome, Fragile X syndrome, Simpson-Golabi-Behmel syndrome and 22qter deletion syndrome. Management is multidisciplinary. During the neonatal period, therapies are mostly symptomatic, including phototherapy in case of jaundice, treatment of the feeding difficulties and gastroesophageal reflux, and detection and treatment of hypoglycemia. General pediatric follow-up is important during the first years of life to allow detection and management of clinical complications such as scoliosis and febrile seizures. An adequate psychological and educational program with speech therapy and motor stimulation plays an important role in the global development of the patients. Final body height is difficult to predict but growth tends to normalize after puberty.

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Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice.

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