Cadherin 8 regulates proliferation of cortical interneuron progenitors

Memi, Fani; Killen, Abigail C.; Barber, Melissa; Parnavelas, John G.; Andrews, William

doi:10.1007/s00429-018-1772-4

Cited by 10 publications

(6 citation statements)

References 57 publications

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“…6C). Western blots of regional dissections taken from littermates show near complete loss of Cdh8 in PFC (the remainder is consistent with low levels of Cdh8 reported in inhibitory neurons 27 ), but unchanged Cdh8 expression levels in striatum as expected (Fig. 6D).…”

Section: Resultssupporting

confidence: 87%

Development of prefrontal corticostriatal connectivity in mice

Mesias¹,

Zaki²,

Guevara³

et al. 2023

Preprint

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Rational decision making is grounded in learning to associate actions with outcomes, a process that depends on projections from prefrontal cortex to dorsomedial striatum. Symptoms associated with a variety of human pathological conditions ranging from schizophrenia and autism to Huntington's and Parkinson's disease point toward functional deficits in this projection, but its development is not well understood, making it difficult to investigate how perturbations in development of this circuitry could contribute to pathophysiology. We applied a novel strategy based on Hotspot Analysis to assess the developmental progression of anatomical positioning of prefrontal cortex to striatal projections. Corticostriatal axonal territories established at P7 expand in concert with striatal growth but remain largely unchanged in positioning through adulthood, indicating they are generated by directed, targeted growth and not modified extensively by postnatal experience. Consistent with these findings, corticostriatal synaptogenesis increased steadily from P7 to P56, with no evidence for widescale pruning. As corticostriatal synapse density increased over late postnatal ages, the strength of evoked PFC input onto dorsomedial striatal projection neurons also increased, but spontaneous glutamatergic synaptic activity was stable. Based on its pattern of expression, we asked whether the adhesion protein, Cdh8, influenced this progression. In mice lacking Cdh8 in PFC corticostriatal projection neurons, axon terminal fields in dorsal striatum shifted ventrally. Corticostriatal synaptogenesis was unimpeded, but spontaneous EPSC frequency declined and mice failed to learn to associate an action with an outcome. Collectively these findings show that corticostriatal axons grow to their target zone and are restrained from an early age, do not undergo postnatal synapse pruning as the most dominant models predict, and that a relatively modest shift in terminal arbor positioning and synapse function has an outsized, negative impact on corticostriatal-dependent behavior.

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Section: Resultssupporting

confidence: 87%

Development of prefrontal corticostriatal connectivity in mice

Mesias¹,

Zaki²,

Guevara³

et al. 2023

Preprint

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“…Interestingly, some of these alterations, including the reduced expression of proteins involved in cell adhesion such as Cdh8 and Neo1, could be related with the expansion in neurogenesis that we observed during development. Indeed, Cdh8 is expressed in the germinal zone during development, and its knockdown amplifies both proliferation and neuron numbers 57 . Similarly, genetic ablation of Neo1 also increases proliferation 58 .…”

Section: Discussionmentioning

confidence: 99%

Expansion of the neocortex and protection from neurodegeneration byin vivotransient reprogramming

Shen,

Zaballa,

Bech

et al. 2023

Preprint

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SummaryYamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatio-temporal manner in two different scenarios: brain development, and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells during development. Under these conditions, YFs induction led to expanded neurogenesis, increased number of upper cortical neurons, and enhanced motor and social behavior of adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimer’s disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. Overall, these results highlight the powerful impact of YFs on neurogenesis and their potential use in brain disorders.HighlightsTransient Yamanaka factor (YF) expression during development expands neocortexYF-treated mice show enhanced cognitive skillsIntermitent YF expression is tolerated by adult principal hippocampal neuronsLong-term intermitent YF reprogramming is protective in an AD mouse model

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“…Newly postmitotic cells that will become cortical interneurons express the LIM homeobox gene Lhx6 and cadherin-8 (Cdh8) already within the subpallial medial ganglionic eminence. Mice lacking Cdh8 displayed a significant increase in the number of cortical interneurons and in vitro studies confirmed that knockdown of Cdh8 induced proliferation of neural progenitors, whereas over expression of Cdh8 resulted in decreased proliferation (Memi et al, 2019). Interneuron progenitors also express the neuropilin receptors Nrp1 and Nrp2 which mediate their response to semaphorin (Sema) 3 ligands.…”

Section: Neurogenesis In the Mammalian Neocortexmentioning

confidence: 94%

Birth and death of neurons in the developing and mature mammalian brain

Dori¹,

Bekiari²,

Grivas³

et al. 2022

Int. J. Dev. Biol.

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Neuron birth and death are two contradictory processes, yet serving the same purpose of the formation of the brain. They coexist during brain development, when cytoarchitecture and synaptic contacts are progressively established. It is the highly programmed interplay between these two processes that results in the making of a mature, complex-wired, functional brain. Neurogenesis is the process that begins with the birth of naïve new neurons, which are gradually specified to their prospective cell fate, translocate through migratory streams to the brain area they are destined for and terminally differentiate into mature neurons that integrate into neuronal networks with sophisticated functions. This is an ongoing process until adulthood, when it mediates brain neuroplasticity. Neuron death is the process through which the fine sculpting and modeling of the brain is achieved. It serves to adjust final neuron numbers, exerting quality control on neurons that birth has generated or overproduced. It additionally corrects early wiring and performs systems matching by negatively selecting neurons that fail to gain neurotransmitter-mediated neuronal activity or receive neurotrophic support for maintenance and function. It is also a means by which organizing centers and transient structures are removed early in morphogenesis. Both processes are evolutionary conserved, genetically programmed and orchestrated by the same signaling factors regulating the cell cycle, neuronal activity/neurotransmitter action and neurotrophic support. This review summarizes and highlights recent knowledge on birth and death of neurons, the two mutually dependent contributors to the formation of the highly evolved mammalian brain.

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Cadherin 8 regulates proliferation of cortical interneuron progenitors

Cited by 10 publications

References 57 publications

Development of prefrontal corticostriatal connectivity in mice

Development of prefrontal corticostriatal connectivity in mice

Expansion of the neocortex and protection from neurodegeneration byin vivotransient reprogramming

Birth and death of neurons in the developing and mature mammalian brain

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