Dr Isabel Martinez Garay

Publication

• Date
• Type

Research

The cerebral cortex is the seat of higher brain function and it plays a key role in memory, attention, thought, perception, language, human consciousness, etc. Disruption of its layered architecture and alteration of its circuitry are associated with many neurological disorders, including epilepsy, schizophrenia, autism and mental retardation. Our long-term objective is to understand the cellular and molecular mechanisms of circuit formation in the cortex and how disruption of these processes leads to neuronal and brain dysfunction.

During cortical development different steps need to be tightly regulated and coordinated in order to obtain a mature, six-layered structure. Progenitors at the ventricular zone have to generate specific types of neurons at the appropriate time and in correct numbers. These neurons then migrate into the nascent cortical plate while simultaneously extending their axons and, once they arrive at their final position in the right layer, they start to elaborate the dendritic arbor and establish synaptic contacts with specific targets (Figure 1). These processes involve a great deal of cell-cell contact and recognition, and the cadherin superfamily with its high diversity is especially suited to fulfil these functions.

Cadherins are transmembrane proteins that contain variable numbers of tandem extracellular cadherin repeats (ECs). Although initially identified as calcium-dependent cell-cell adhesion proteins, it has become clear that members of this superfamily exhibit great functional diversity, with roles in signaling, mechanotransduction and development. Protocadherins represent the largest family within the cadherin superfamily and they show predominant expression in the nervous system. We are particularly interested in a group of non-clustered protocadherins: the delta protocadherins. They are single transmembrane proteins with 7 (delta-1) or 6 (delta-2) EC repeats.

Analysis of the involvement of delta-protocadherins in neurogenesis, migration and/or synaptogenesis

With the mouse as a model system, we use a variety of techniques to study cortical development both in vitro and in vivo.  We employ molecular and cell biological approaches, and combine them with techniques such as in utero electroporation and primary neuronal cultures, to manipulate protocadherin function and assess the effects of such manipulations on neuronal production, positioning, target specificity and connectivity. We also aim to characterize the spatio-temporal expression pattern of the different delta-protocadherins. We want to analyze which cell types express delta protocadherins in the embryonic and postnatal brains and how the expression pattern changes over time. This information is key to predict potential roles for the different proteins.

In utero electroporation allows delivery of DNA plasmids to the neural progenitors that line the ventricles, which then pass these plasmids on to their neuronal or glial progeny. Variations in the design of those plasmids (different promotors, cre-dependency, genomic insertion capability, etc.) lead to many different applications.  As a result, in utero electroporation has proven to be a very versatile technique in the cortical development field, with the key advantage of allowing processes to be studied in vivo (Figure 2).

Pathological mechanisms underlying Pcdh19 epilepsy

One of the delta-2 protocadherins, Pcdh19, is mutated in Juberg-Hellman syndrome (also known as Pcdh19 epilepsy or EIEE9), in which affected females show seizure onset in infancy or early childhood and cognitive impairment. The PCDH19 gene is located on the X-chromosome and the disorder follows an X-linked inheritance, but only heterozygous females are affected, whereas hemizygous transmitting males are spared. The random inactivation of the X chromosome in females results in the developing brain consisting of a mixed population of neurons expressing or lacking the protein, and as homozygotes are less affected than heterozygotes, it is possible that Pcdh19 might be involved in non-cell autonomous functions such as synapse formation. In addition, the early disease onset combined with an early expression in proliferative zones of the developing brain open the possibility of additional roles for Pcdh19 in neurogenesis or migration. To date, the only functional information about Pcdh19 comes from zebrafish, where the protein is necessary for embryonic neurulation. In this system, Pcdh19 forms a complex with N-cadherin and regulates cell movement. However, the function of Pcdh19 during cortical development in mammals remains to be determined.

Figure 1

Schematic representation of the different processes taking place during cortical development.

Figure 2

Example of an in utero electroporation with a control plasmid and two different mutant proteins. Brains were electroporated at E14.5 and analyzed 4 days later. In the control, electroporated neurons have migrated to the top of the nascent cortical plate. In contrast, both mutated proteins impair migration and neurons are still widely distributed across the cortical wall.

Current lab members:

Dr Cristina Llinares Benadero (Postdoc)

Dr Blanca Paramo (Postdoc)

Sylvia Adriana Newbold (PhD Student)

Ian W. Fox (PhD Student)

Monika Sledziowska (PhD Student)

Lab Alumni:

Dr Jessica Griffiths

Dr Natalia Galindo-Riera

James Wilding

Teaching

In academic year 2021-22, my current teaching includes contributions to the following modules:

BI2432  Fundamental Neuroscience (Developmental Neuroscience)

BI3451 Neurobiology of brain disorders (Neurodevelopmental Disorders: ASD and Cognitive Impairment)

BI3001 Biosciences Final Year Project (Supervision)

CN0070 - CPD20N0070A GW4 BioMed Core Skills (Postgraduate)

Other contributions in previous years:

BI3256 Current topics in Development, Stem Cells and Repair (Embryonic and Adult Neurogenesis and Neural Stem Cells in different organisms; Module Assessment Coordinator)

Biography

After completing a 5-year Biology degree from the University of Valencia (Spain), I spent 13 months working at the Human Genetics Institute at the University Hospital Hamburg-Epperndorf in Germany. I then started two paralllel PhD projects in both institutions, focusing on X-linked cognitive impairment (Valencia) and the characterization of novel genes affected by a chromosomal rearrangement (Hamburg). After finishing my PhDs, I decided to move into the field of Developmental Neuroscience for my postdoc at the Scripps Research Institute in La Jolla, California, where I started investigating neurogenesis, fate specification and neuronal migration during development of the cerebral cortex. My work then continued in the group of Prof Zoltan Molnar at the University of Oxford, where I studied the roles of a dyslexia susceptibility gene during cortical development.

In 2015 I moved to Cardiff, where my laboratory focuses on cell-cell adhesion and communication during brain development and, in particular, on the role of different members of the cadherin superfamily.

Honours and awards

• Burgen Scholarship Award (Academia Europaea) (2016)
• Postdoctoral Fellowship, CIRM (California Institute for Regenerative Medicine) (2009-2012)
• MEC/Fulbright Postdoctoral Fellowship, Spanish Ministry of Education (2007-2008)
• FPU Doctoral Fellowship, Spanish Ministry of Education (2000-2003)            
• DAAD Fellowship, German Academic Exchange Service (1998-1999)

Professional memberships

• British Neuroscience Association, Member (since 2020)
• Society for Neuroscience, Member (since 2007)
• Spanish Society of Human Genetics, Member (since 2001)
• Spanish Genetics Society, Member (since 2003)

Academic positions

• 2018 - present: University Senior Lecturer, Cardiff University, UK
• 2015 - 2018: University Lecturer, Cardiff University, UK
• 2012 - 2015: Senior Research Associate, University of Oxford, UK
• 2007 - 2012: Research Associate, The Scripps Research Institute, La Jolla, CA, USA
• 2003 - 2007: Graduate Student, University Hospital Hamburg- Eppendorf, Hamburg, Germany
• 2005 - 2006: Postdoctoral Researcher, University Hospital La Fe, Valencia, Spain
• 2000 - 2005: Graduate Student, University of Valencia, Spain
• 1998 - 1999: DAAD Fellow, University Hospital Hamburg- Eppendorf, Hamburg, Germany 

Committees and reviewing

• Review Editor for Neurogenesis, Frontiers in Neuroscience
• Guest editor for JoVE
• Grant reviewer, BBSRC, MRC, ISSF3
• Reviewer: Development, Molecular Neuroscience, PNAS
• REF Output reviewer for BIOSI
• Athena Swan Committee member

Supervisions

I am interested in supervising PhD students in the area of Neural development, including neurogenesis and neural stem cells, fate specification, migration and circuit formation.

My current PhD students are:

• Ian W. Fox