Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression

Abstract

Psychiatric disorders are associated with aberrant brain development and/or aggressive behavior and are influenced by genetic factors; however, genes that affect brain aggression circuits remain elusive. Here, we show that neuronal Src-homology-2 (SH2)B adaptor protein-1 ( Sh2b1) is indispensable for both brain growth and protection against aggression. Global and brain-specific deletion of Sh2b1 decreased brain weight and increased aggressive behavior. Global and brain-specific Sh2b1 knockout (KO) mice exhibited fatal, intermale aggression. In a resident-intruder paradigm, latency to attack was markedly reduced, whereas the number and the duration of attacks was significantly increased in global and brain-specific Sh2b1 KO mice compared with wild-type littermates. Consistently, core aggression circuits were activated to a higher level in global and brain-specific Sh2b1 KO males, based on c-fos immunoreactivity in the amygdala and periaqueductal gray. Brain-specific restoration of Sh2b1 normalized brain size and reversed pathologic aggression and aberrant activation of core aggression circuits in Sh2b1 KO males. SH2B1 mutations in humans were linked to aberrant brain development and behavior. At the molecular level, Sh2b1 enhanced neurotrophin-stimulated neuronal differentiation and protected against oxidative stress-induced neuronal death. Our data suggest that neuronal Sh2b1 promotes brain development and the integrity of core aggression circuits, likely through enhancing neurotrophin signaling.-Jiang, L., Su, H., Keogh, J. M., Chen, Z., Henning, E., Wilkinson, P., Goodyer, I., Farooqi, I. S., Rui, L. Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression.

Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease

“…4c). In line with these findings, Sh2b1 protein is detected in the entire brain by immunoblotting 16 . To confirm that proopiomelanocortin (POMC) and AgRP neurons express Sh2b1, hypothalamic sections were prepared from Sh2b1-Cre;mTmG mice and immunostained with antibodies to POMC and AgRP.…”

“…We recently reported that neuronal Sh2b1 promotes brain development 16 . To distinguish between brain development-dependent and -independent actions of Sh2b1 on body weight and metabolism, we generated adult-onset, hypothalamus-specific Sh2b1 knockout mice by bilaterally microinjecting AAV1-hSyn-Cre vectors into the mediobasal hypothalami (MBH) of Sh2b1 f/f males at 10 weeks of age.…”

“…However, we do not exclude the possibility that Sh2b1 in LepR neurons may promote SNS activity and maintenance by additional mechanisms. For instance, Sh2b1 enhances BDNF and insulin signaling in cell cultures [16][17][18]53 . BDNF and insulin, like leptin, also activate the SNS/BAT energy expenditure axis [16][17][18]54,55 .…”

“…Sh2b1 also binds to IRS1 and IRS2 and links JAK2 to IRS1/2-mediated activation of the PI 3-kinase pathway in cell cultures 13 . Aside from JAK2, Sh2b1 also binds to receptor tyrosine kinases, including insulin receptors, platelet-derived growth factor receptors, nerve growth factor receptor TrkA, and brain-derived neurotrophic factor (BDNF) receptor TrkB [16][17][18][19][20][21][22] . To examine Sh2b1 function in vivo, we generate and characterize global Sh2b1 knockout mice.…”

Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance

“…1 A ). Eleven variants are newly identified, while four (R227C, R270W, E299G, V209I) have been previously reported in other obese individuals but not well characterized ( 4 , 38 , 39 ). Fourteen of these variants are in the first 631 amino acids shared by all isoforms of SH2B1.…”