RESUMO
The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
Assuntos
Astrócitos/metabolismo , Corpo Caloso/metabolismo , Receptor DCC/metabolismo , Telencéfalo/metabolismo , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/metabolismo , Agenesia do Corpo Caloso/patologia , Animais , Células COS , Linhagem Celular Tumoral , Movimento Celular , Forma Celular , Chlorocebus aethiops , Corpo Caloso/embriologia , Receptor DCC/genética , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Idade Gestacional , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese , Mutação , Netrina-1/genética , Netrina-1/metabolismo , Fenótipo , Transdução de Sinais , Telencéfalo/embriologiaRESUMO
Natural killer (NK) cells are an important component of the innate immune system, particularly for metastasis immunosurveillance. They can rapidly recognize and kill transformed cells without the requirement of specific neo-antigen recognition. Their effector functions are modulated by a range of stimulatory and inhibitory surface receptors that regulate their cellular activation, differentiation and homeostasis. However, cancer cells can evade NK cell detection by receptor interaction or secretion of soluble immunosuppressant molecules. Therefore, genetic reprogramming of these immune suppressing or activating receptors of NK cells is a promising strategy to augment NK cell tumoricidal functions. In this review, we highlight the current clinical trials of chimeric antigen receptor engineered NK cells with redirected antigen specificity to eliminate hematological cancers and solid tumors. New alternative strategies that are advancing NK cell engineering for cancer treatment are also outlined. Lastly, different NK cell transgenesis approaches are reviewed and compared, and we discuss how these methods can be employed to maximize their anti-tumor effector functions.
Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Humanos , Neoplasias/imunologiaRESUMO
Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.