Delayed cortical development in mice with a neural specific deletion of β1 integrin

Abstract

The adhesion systems employed by migrating cortical neurons are not well understood. Genetic deletion studies of focal adhesion kinase (FAK) and paxillin in mice suggested that these classical focal adhesion molecules control the morphology and speed of cortical neuron migration, but whether β1 integrins also regulate migration morphology and speed is not known. We hypothesized that a β1 integrin adhesion complex is required for proper neuronal migration and for proper cortical development. To test this, we have specifically deleted β1 integrin from postmitotic migrating and differentiating neurons by crossing conditional β1 integrin floxed mice into the NEX-Cre transgenic line. Similar to our prior findings with conditional paxillin deficiency, we found that both homozygous and heterozygous deletion of β1 integrin causes transient mispositioning of cortical neurons in the developing cortex when analyzed pre- and perinatally. Paxillin and β1 integrin colocalize in the migrating neurons and deletion of paxillin in the migrating neuron causes an overall reduction of the β1 integrin immunofluorescence signal and reduction in the number of activated β1 integrin puncta in the migrating neurons. These findings suggest that these molecules may form a functional complex in migrating neurons. Similarly, there was an overall reduced number of paxillin+ puncta in the β1 integrin deficient neurons, despite the normal distribution of FAK and Cx26, a connexin required for cortical migration. The double knockout of paxillin and β1 integrin produces a cortical malpositioning phenotype similar to the paxillin or β1 integrin single knockouts, as would be expected if paxillin and β1 integrin function on a common pathway. Importantly, an isolation-induced pup vocalization test showed that β1 integrin mutants produced a significantly smaller number of calls compared to their littermate controls when analyzed at postnatal day 4 (P4) and revealed a several days trend in reduced vocalization development compared to controls. The current study establishes a role for β1 integrin in cortical development and suggests that β1 integrin deficiency leads to migration and neurodevelopmental delays.

Analysis of single nuclear chromatin accessibility reveals unique myeloid populations in human pancreatic ductal adenocarcinoma

“…Furthermore, FGF9 and FGF10 , genes recently shown to be involved in pancreatic development 59 and previously known to be important for neuronal development and maturation 60 play a role in the GO pathway developmental growth for the acinar cell cluster. In the endocrine cluster, the GO pathway neuron projection morphogenesis is characterised by Pax6 , a gene responsible for development of the pancreas and other neuroectodermal structures, 61 ISL1 , a gene important for beta cell function, 62 and ITGB1 , a gene coding for an integrin critical for islet cell development in the pancreas 63 and for neuronal cell migration 64 . ADM GO enrichment includes cell–cell junctions and adhesions, representing the transition of acinar cells to a more ductal‐like phenotype 15 .…”

“…In the endocrine cluster, the GO pathway neuron projection morphogenesis is characterised by Pax6, a gene responsible for development of the pancreas and other neuroectodermal structures, 61 ISL1, a gene important for beta cell function, 62 and ITGB1, a gene coding for an integrin critical for islet cell development in the pancreas 63 and for neuronal cell migration. 64 ADM GO enrichment includes cell-cell junctions and adhesions, representing the transition of acinar cells to a more ductal-like phenotype. 15 In the ADM GO enrichment, PCDH1, a negative prognostic indicator in PDAC 65,66 is one of the genes for homophilic cell adhesion via plasma membrane adhesion molecules.…”

Morphogenetic theory of mental and cognitive disorders: the role of neurotrophic and guidance molecules

“…Among the key positive signals are: neurotrophic factor GGF2 (glial growth factor-2, a soluble form of neuregulin1)/erbB2, adhesion molecule CDH2 (N-cadherin) expressed on the surface of radial glial cells, and neurotransmitters Glutamate (signals via GRIN2A), GABA (signals via GABRA1 or GABBR1) (Anton et al, 1997;Luhmann et al, 2015). Experimental findings provide compelling evidence that CDH2 and αVβ1 integrin expression on the plasma membrane of postmitotic neurons are essentially important for their migration (Meyerink et al, 2020;Rashid and Olson, 2023). Soluble proteins, including Reelin, SPARClike-1, and others distributed within the marginal zone and along the upper boundary of the cortical plate, provide inhibitory signals that restrict the radial neuron migration (Chai and Frotscher, 2016).…”