As summarized in this Review and in , recent studies reveal a complex control of dendrite pattern, size and maintenance involving various transcription factors, cell surface receptors, signalling cascades, regulators of cytoskeletal elements, and the secretory and endocytic pathways. In addition, dendrite morphology is modulated by signalling with other neurons as well as other cell types. Although we are still far from having a coherent mechanistic understanding, much of the progress made to date has been due to the identification of genes involved in dendrite morphogenesis that has allowed the formulation of more precise questions.
Many questions await further studies, including how dendrites signal to one another during tiling and how dendrite growth is coordinated to match body growth. In addition, because dendrites are highly compartmentalized, an important area of research is the regulation of the expression and dendritic localization of various signalling molecules. Molecular and cellular analyses of dendrite patterning, pruning and maintenance may also provide clues as to whether some mental disorders involve dysregulation of dendrite morphogenesis or maintenance, as discussed below.
Trans-heterozygosity could cause mental disorders
Studies of the mechanisms controlling dendrite formation, maintenance and pruning of D. melanogaster
dendritic arborization neurons25
have identified an unexpectedly large number (probably more than 100) of genes146,147
(). Abnormalities in dendrite growth or pruning could contribute to mental disorders such as autism, which manifests in early childhood, and schizophrenia, which develops in late adolescence, both of which are heritable mental disorders with a largely unknown genetic basis (BOX 3
). Genetic studies of dendrite morphogenesis and maintenance may therefore suggest possible mediators of these diseases. These complex mental disorders are likely to be large conglomerates of rare and genetically diverse diseases. The trans-heterozygous combination of mutations of two genes that individually (in heterozygotes) do not have a discernable effect on phenotype could compromise dendrite morphogenesis and result in mental disorders. A strong interaction between two gene products in the same pathway is evident when a reduction in the activity of both — but not of either one alone — results in mutant phenotypes, as is the case for genes of the Hippo pathway and Polycomb group that have key roles for dendrite stability146,147
. It would be interesting to test whether trans-heterozygous mutant combinations in humans (either transmitted from parents or de novo
mutations) could be the cause of some of the mental disorders that have a complex genetic basis. With current technologies, it is challenging to conduct genome-wide association studies of interacting genes that, in combination, cause mental disorders. It is more practical to attempt deep sequencing to look for mutations of human candidate genes that are homologous to those identified through genetic studies of dendrite morphogenesis in D. melanogaster
. These studies should aim to identify alterations of these genes that, alone or in combination, associate with neurodevelopmental disorders such as autism and schizophrenia.
Box 3. Dendrite abnormalities in human diseases
Human cortical neurons start growing dendrites soon after they have entered their destined cortical layer155
. With the arrival of thalamic or cortical afferent fibres and the expression of NMDA (N
-methyl-d-aspartate) receptors, pyramidal neurons undergo a second phase of dendrite branching and extension until the third postnatal month156
. Whereas layer V pyramidal neurons in the prefrontal cortex reach peak dendrite complexity between the third and sixteenth postnatal months, layer IIIC pyramidal neurons seem dormant during this period, and resume dendrite growth over the next 14 months156
. The number of synapses and spines also approaches a maximum in early childhood, followed by synaptic pruning in adolescence10
. Intriguingly, intellectual ability seems to correlate with an accelerated and prolonged increase of cortical thickness in childhood followed by equally vigorous cortical thinning in adolescence157
. As discussed below, dendrite development shows strong temporal correlation with the emergence of behavioural symptoms of several mental disorders.
Mental disorders such as autism3–5
and Rett’s syndrome7
are often associated with abnormal brain size, suggesting overgrowth or lack of dendrite pruning as well as alterations of neuronal number during development. The emergence of behavioural symptoms in the first 3 years of life further begs the question whether abnormal dendrite morphogenesis contributes to these neurodevelopmental disorders. Single gene mutations linked to diseases such as Rett’s syndrome, Angelman’s syndrome, tuberous sclerosis and fragile X syndrome are known to greatly increase the risk for autism. However, the genetic underpinning of autism remains elusive in most cases despite the high heritability4,10,53,158
In contrast to mental disorders with early manifestation of macrocephaly and behavioural symptoms, which may arise from overgrowth or lack of dendrite pruning in early childhood, schizophrenia could arise from over-pruning or failed maintenance of dendrites later in life. Notably, recent MRI studies reveal progressive grey-matter loss before and during psychosis development in schizophrenia in late adolescence, suggesting synaptic over-pruning9,159
. Despite the heritability of schizophrenia160
and associated progressive brain volume changes161
, and the linkage of schizophrenia to mutations of neuregulin 1 and its receptor159,162
, the genetic basis for schizophrenia remains largely unknown163